IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5207T>C (p.Val1736Ala)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Jun 2019 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.5207T>C (p.Val1736Ala)
Variation ID: 37648 Accession: VCV000037648.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43057122 (GRCh38) [ NCBI UCSC ] 17: 41209139 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 1, 2014 Jun 17, 2024 Jun 25, 2019 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5207T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Val1736Ala missense NM_001407571.1:c.4994T>C NP_001394500.1:p.Val1665Ala missense NM_001407581.1:c.5273T>C NP_001394510.1:p.Val1758Ala missense NM_001407582.1:c.5273T>C NP_001394511.1:p.Val1758Ala missense NM_001407583.1:c.5270T>C NP_001394512.1:p.Val1757Ala missense NM_001407585.1:c.5270T>C NP_001394514.1:p.Val1757Ala missense NM_001407587.1:c.5270T>C NP_001394516.1:p.Val1757Ala missense NM_001407590.1:c.5267T>C NP_001394519.1:p.Val1756Ala missense NM_001407591.1:c.5267T>C NP_001394520.1:p.Val1756Ala missense NM_001407593.1:c.5207T>C NP_001394522.1:p.Val1736Ala missense NM_001407594.1:c.5207T>C NP_001394523.1:p.Val1736Ala missense NM_001407596.1:c.5207T>C NP_001394525.1:p.Val1736Ala missense NM_001407597.1:c.5207T>C NP_001394526.1:p.Val1736Ala missense NM_001407598.1:c.5207T>C NP_001394527.1:p.Val1736Ala missense NM_001407602.1:c.5207T>C NP_001394531.1:p.Val1736Ala missense NM_001407603.1:c.5207T>C NP_001394532.1:p.Val1736Ala missense NM_001407605.1:c.5207T>C NP_001394534.1:p.Val1736Ala missense NM_001407610.1:c.5204T>C NP_001394539.1:p.Val1735Ala missense NM_001407611.1:c.5204T>C NP_001394540.1:p.Val1735Ala missense NM_001407612.1:c.5204T>C NP_001394541.1:p.Val1735Ala missense NM_001407613.1:c.5204T>C NP_001394542.1:p.Val1735Ala missense NM_001407614.1:c.5204T>C NP_001394543.1:p.Val1735Ala missense NM_001407615.1:c.5204T>C NP_001394544.1:p.Val1735Ala missense NM_001407616.1:c.5204T>C NP_001394545.1:p.Val1735Ala missense NM_001407617.1:c.5204T>C NP_001394546.1:p.Val1735Ala missense NM_001407618.1:c.5204T>C NP_001394547.1:p.Val1735Ala missense NM_001407619.1:c.5204T>C NP_001394548.1:p.Val1735Ala missense NM_001407620.1:c.5204T>C NP_001394549.1:p.Val1735Ala missense NM_001407621.1:c.5204T>C NP_001394550.1:p.Val1735Ala missense NM_001407622.1:c.5204T>C NP_001394551.1:p.Val1735Ala missense NM_001407623.1:c.5204T>C NP_001394552.1:p.Val1735Ala missense NM_001407624.1:c.5204T>C NP_001394553.1:p.Val1735Ala missense NM_001407625.1:c.5204T>C NP_001394554.1:p.Val1735Ala missense NM_001407626.1:c.5204T>C NP_001394555.1:p.Val1735Ala missense NM_001407627.1:c.5201T>C NP_001394556.1:p.Val1734Ala missense NM_001407628.1:c.5201T>C NP_001394557.1:p.Val1734Ala missense NM_001407629.1:c.5201T>C NP_001394558.1:p.Val1734Ala missense NM_001407630.1:c.5201T>C NP_001394559.1:p.Val1734Ala missense NM_001407631.1:c.5201T>C NP_001394560.1:p.Val1734Ala missense NM_001407632.1:c.5201T>C NP_001394561.1:p.Val1734Ala missense NM_001407633.1:c.5201T>C NP_001394562.1:p.Val1734Ala missense NM_001407634.1:c.5201T>C NP_001394563.1:p.Val1734Ala missense NM_001407635.1:c.5201T>C NP_001394564.1:p.Val1734Ala missense NM_001407636.1:c.5201T>C NP_001394565.1:p.Val1734Ala missense NM_001407637.1:c.5201T>C NP_001394566.1:p.Val1734Ala missense NM_001407638.1:c.5201T>C NP_001394567.1:p.Val1734Ala missense NM_001407639.1:c.5201T>C NP_001394568.1:p.Val1734Ala missense NM_001407640.1:c.5201T>C NP_001394569.1:p.Val1734Ala missense NM_001407641.1:c.5201T>C NP_001394570.1:p.Val1734Ala missense NM_001407642.1:c.5201T>C NP_001394571.1:p.Val1734Ala missense NM_001407644.1:c.5198T>C NP_001394573.1:p.Val1733Ala missense NM_001407645.1:c.5198T>C NP_001394574.1:p.Val1733Ala missense NM_001407646.1:c.5195T>C NP_001394575.1:p.Val1732Ala missense NM_001407647.1:c.5192T>C NP_001394576.1:p.Val1731Ala missense NM_001407648.1:c.5150T>C NP_001394577.1:p.Val1717Ala missense NM_001407649.1:c.5147T>C NP_001394578.1:p.Val1716Ala missense NM_001407652.1:c.5129T>C NP_001394581.1:p.Val1710Ala missense NM_001407653.1:c.5129T>C NP_001394582.1:p.Val1710Ala missense NM_001407654.1:c.5129T>C NP_001394583.1:p.Val1710Ala missense NM_001407655.1:c.5129T>C NP_001394584.1:p.Val1710Ala missense NM_001407656.1:c.5126T>C NP_001394585.1:p.Val1709Ala missense NM_001407657.1:c.5126T>C NP_001394586.1:p.Val1709Ala missense NM_001407658.1:c.5126T>C NP_001394587.1:p.Val1709Ala missense NM_001407659.1:c.5123T>C NP_001394588.1:p.Val1708Ala missense NM_001407660.1:c.5123T>C NP_001394589.1:p.Val1708Ala missense NM_001407661.1:c.5123T>C NP_001394590.1:p.Val1708Ala missense NM_001407662.1:c.5123T>C NP_001394591.1:p.Val1708Ala missense NM_001407663.1:c.5123T>C NP_001394592.1:p.Val1708Ala missense NM_001407664.1:c.5084T>C NP_001394593.1:p.Val1695Ala missense NM_001407665.1:c.5084T>C NP_001394594.1:p.Val1695Ala missense NM_001407666.1:c.5084T>C NP_001394595.1:p.Val1695Ala missense NM_001407667.1:c.5084T>C NP_001394596.1:p.Val1695Ala missense NM_001407668.1:c.5084T>C NP_001394597.1:p.Val1695Ala missense NM_001407669.1:c.5084T>C NP_001394598.1:p.Val1695Ala missense NM_001407670.1:c.5081T>C NP_001394599.1:p.Val1694Ala missense NM_001407671.1:c.5081T>C NP_001394600.1:p.Val1694Ala missense NM_001407672.1:c.5081T>C NP_001394601.1:p.Val1694Ala missense NM_001407673.1:c.5081T>C NP_001394602.1:p.Val1694Ala missense NM_001407674.1:c.5081T>C NP_001394603.1:p.Val1694Ala missense NM_001407675.1:c.5081T>C NP_001394604.1:p.Val1694Ala missense NM_001407676.1:c.5081T>C NP_001394605.1:p.Val1694Ala missense NM_001407677.1:c.5081T>C NP_001394606.1:p.Val1694Ala missense NM_001407678.1:c.5081T>C NP_001394607.1:p.Val1694Ala missense NM_001407679.1:c.5081T>C NP_001394608.1:p.Val1694Ala missense NM_001407680.1:c.5081T>C NP_001394609.1:p.Val1694Ala missense NM_001407681.1:c.5078T>C NP_001394610.1:p.Val1693Ala missense NM_001407682.1:c.5078T>C NP_001394611.1:p.Val1693Ala missense NM_001407683.1:c.5078T>C NP_001394612.1:p.Val1693Ala missense NM_001407684.1:c.5207T>C NP_001394613.1:p.Val1736Ala missense NM_001407685.1:c.5078T>C NP_001394614.1:p.Val1693Ala missense NM_001407686.1:c.5078T>C NP_001394615.1:p.Val1693Ala missense NM_001407687.1:c.5078T>C NP_001394616.1:p.Val1693Ala missense NM_001407688.1:c.5078T>C NP_001394617.1:p.Val1693Ala missense NM_001407689.1:c.5078T>C NP_001394618.1:p.Val1693Ala missense NM_001407690.1:c.5075T>C NP_001394619.1:p.Val1692Ala missense NM_001407691.1:c.5075T>C NP_001394620.1:p.Val1692Ala missense NM_001407692.1:c.5066T>C NP_001394621.1:p.Val1689Ala missense NM_001407694.1:c.5066T>C NP_001394623.1:p.Val1689Ala missense NM_001407695.1:c.5066T>C NP_001394624.1:p.Val1689Ala missense NM_001407696.1:c.5066T>C NP_001394625.1:p.Val1689Ala missense NM_001407697.1:c.5066T>C NP_001394626.1:p.Val1689Ala missense NM_001407698.1:c.5066T>C NP_001394627.1:p.Val1689Ala missense NM_001407724.1:c.5066T>C NP_001394653.1:p.Val1689Ala missense NM_001407725.1:c.5066T>C NP_001394654.1:p.Val1689Ala missense NM_001407726.1:c.5066T>C NP_001394655.1:p.Val1689Ala missense NM_001407727.1:c.5066T>C NP_001394656.1:p.Val1689Ala missense NM_001407728.1:c.5066T>C NP_001394657.1:p.Val1689Ala missense NM_001407729.1:c.5066T>C NP_001394658.1:p.Val1689Ala missense NM_001407730.1:c.5066T>C NP_001394659.1:p.Val1689Ala missense NM_001407731.1:c.5066T>C NP_001394660.1:p.Val1689Ala missense NM_001407732.1:c.5063T>C NP_001394661.1:p.Val1688Ala missense NM_001407733.1:c.5063T>C NP_001394662.1:p.Val1688Ala missense NM_001407734.1:c.5063T>C NP_001394663.1:p.Val1688Ala missense NM_001407735.1:c.5063T>C NP_001394664.1:p.Val1688Ala missense NM_001407736.1:c.5063T>C NP_001394665.1:p.Val1688Ala missense NM_001407737.1:c.5063T>C NP_001394666.1:p.Val1688Ala missense NM_001407738.1:c.5063T>C NP_001394667.1:p.Val1688Ala missense NM_001407739.1:c.5063T>C NP_001394668.1:p.Val1688Ala missense NM_001407740.1:c.5063T>C NP_001394669.1:p.Val1688Ala missense NM_001407741.1:c.5063T>C NP_001394670.1:p.Val1688Ala missense NM_001407742.1:c.5063T>C NP_001394671.1:p.Val1688Ala missense NM_001407743.1:c.5063T>C NP_001394672.1:p.Val1688Ala missense NM_001407744.1:c.5063T>C NP_001394673.1:p.Val1688Ala missense NM_001407745.1:c.5063T>C NP_001394674.1:p.Val1688Ala missense NM_001407746.1:c.5063T>C NP_001394675.1:p.Val1688Ala missense NM_001407747.1:c.5063T>C NP_001394676.1:p.Val1688Ala missense NM_001407748.1:c.5063T>C NP_001394677.1:p.Val1688Ala missense NM_001407749.1:c.5063T>C NP_001394678.1:p.Val1688Ala missense NM_001407750.1:c.5063T>C NP_001394679.1:p.Val1688Ala missense NM_001407751.1:c.5063T>C NP_001394680.1:p.Val1688Ala missense NM_001407752.1:c.5063T>C NP_001394681.1:p.Val1688Ala missense NM_001407838.1:c.5060T>C NP_001394767.1:p.Val1687Ala missense NM_001407839.1:c.5060T>C NP_001394768.1:p.Val1687Ala missense NM_001407841.1:c.5060T>C NP_001394770.1:p.Val1687Ala missense NM_001407842.1:c.5060T>C NP_001394771.1:p.Val1687Ala missense NM_001407843.1:c.5060T>C NP_001394772.1:p.Val1687Ala missense NM_001407844.1:c.5060T>C NP_001394773.1:p.Val1687Ala missense NM_001407845.1:c.5060T>C NP_001394774.1:p.Val1687Ala missense NM_001407846.1:c.5060T>C NP_001394775.1:p.Val1687Ala missense NM_001407847.1:c.5060T>C NP_001394776.1:p.Val1687Ala missense NM_001407848.1:c.5060T>C NP_001394777.1:p.Val1687Ala missense NM_001407849.1:c.5060T>C NP_001394778.1:p.Val1687Ala missense NM_001407850.1:c.5060T>C NP_001394779.1:p.Val1687Ala missense NM_001407851.1:c.5060T>C NP_001394780.1:p.Val1687Ala missense NM_001407852.1:c.5060T>C NP_001394781.1:p.Val1687Ala missense NM_001407853.1:c.5060T>C NP_001394782.1:p.Val1687Ala missense NM_001407854.1:c.5207T>C NP_001394783.1:p.Val1736Ala missense NM_001407858.1:c.5204T>C NP_001394787.1:p.Val1735Ala missense NM_001407859.1:c.5204T>C NP_001394788.1:p.Val1735Ala missense NM_001407860.1:c.5204T>C NP_001394789.1:p.Val1735Ala missense NM_001407861.1:c.5201T>C NP_001394790.1:p.Val1734Ala missense NM_001407862.1:c.5006T>C NP_001394791.1:p.Val1669Ala missense NM_001407863.1:c.5003T>C NP_001394792.1:p.Val1668Ala missense NM_001407874.1:c.5000T>C NP_001394803.1:p.Val1667Ala missense NM_001407875.1:c.5000T>C NP_001394804.1:p.Val1667Ala missense NM_001407879.1:c.4997T>C NP_001394808.1:p.Val1666Ala missense NM_001407881.1:c.4997T>C NP_001394810.1:p.Val1666Ala missense NM_001407882.1:c.4997T>C NP_001394811.1:p.Val1666Ala missense NM_001407884.1:c.4997T>C NP_001394813.1:p.Val1666Ala missense NM_001407885.1:c.4997T>C NP_001394814.1:p.Val1666Ala missense NM_001407886.1:c.4997T>C NP_001394815.1:p.Val1666Ala missense NM_001407887.1:c.4997T>C NP_001394816.1:p.Val1666Ala missense NM_001407889.1:c.4997T>C NP_001394818.1:p.Val1666Ala missense NM_001407894.1:c.4994T>C NP_001394823.1:p.Val1665Ala missense NM_001407895.1:c.4994T>C NP_001394824.1:p.Val1665Ala missense NM_001407896.1:c.4994T>C NP_001394825.1:p.Val1665Ala missense NM_001407897.1:c.4994T>C NP_001394826.1:p.Val1665Ala missense NM_001407898.1:c.4994T>C NP_001394827.1:p.Val1665Ala missense NM_001407899.1:c.4994T>C NP_001394828.1:p.Val1665Ala missense NM_001407900.1:c.4994T>C NP_001394829.1:p.Val1665Ala missense NM_001407902.1:c.4994T>C NP_001394831.1:p.Val1665Ala missense NM_001407904.1:c.4994T>C NP_001394833.1:p.Val1665Ala missense NM_001407906.1:c.4994T>C NP_001394835.1:p.Val1665Ala missense NM_001407907.1:c.4994T>C NP_001394836.1:p.Val1665Ala missense NM_001407908.1:c.4994T>C NP_001394837.1:p.Val1665Ala missense NM_001407909.1:c.4994T>C NP_001394838.1:p.Val1665Ala missense NM_001407910.1:c.4994T>C NP_001394839.1:p.Val1665Ala missense NM_001407915.1:c.4991T>C NP_001394844.1:p.Val1664Ala missense NM_001407916.1:c.4991T>C NP_001394845.1:p.Val1664Ala missense NM_001407917.1:c.4991T>C NP_001394846.1:p.Val1664Ala missense NM_001407918.1:c.4991T>C NP_001394847.1:p.Val1664Ala missense NM_001407919.1:c.5084T>C NP_001394848.1:p.Val1695Ala missense NM_001407920.1:c.4943T>C NP_001394849.1:p.Val1648Ala missense NM_001407921.1:c.4943T>C NP_001394850.1:p.Val1648Ala missense NM_001407922.1:c.4943T>C NP_001394851.1:p.Val1648Ala missense NM_001407923.1:c.4943T>C NP_001394852.1:p.Val1648Ala missense NM_001407924.1:c.4943T>C NP_001394853.1:p.Val1648Ala missense NM_001407925.1:c.4943T>C NP_001394854.1:p.Val1648Ala missense NM_001407926.1:c.4943T>C NP_001394855.1:p.Val1648Ala missense NM_001407927.1:c.4940T>C NP_001394856.1:p.Val1647Ala missense NM_001407928.1:c.4940T>C NP_001394857.1:p.Val1647Ala missense NM_001407929.1:c.4940T>C NP_001394858.1:p.Val1647Ala missense NM_001407930.1:c.4940T>C NP_001394859.1:p.Val1647Ala missense NM_001407931.1:c.4940T>C NP_001394860.1:p.Val1647Ala missense NM_001407932.1:c.4940T>C NP_001394861.1:p.Val1647Ala missense NM_001407933.1:c.4940T>C NP_001394862.1:p.Val1647Ala missense NM_001407934.1:c.4937T>C NP_001394863.1:p.Val1646Ala missense NM_001407935.1:c.4937T>C NP_001394864.1:p.Val1646Ala missense NM_001407936.1:c.4937T>C NP_001394865.1:p.Val1646Ala missense NM_001407937.1:c.5084T>C NP_001394866.1:p.Val1695Ala missense NM_001407938.1:c.5084T>C NP_001394867.1:p.Val1695Ala missense NM_001407939.1:c.5081T>C NP_001394868.1:p.Val1694Ala missense NM_001407940.1:c.5081T>C NP_001394869.1:p.Val1694Ala missense NM_001407941.1:c.5078T>C NP_001394870.1:p.Val1693Ala missense NM_001407942.1:c.5066T>C NP_001394871.1:p.Val1689Ala missense NM_001407943.1:c.5063T>C NP_001394872.1:p.Val1688Ala missense NM_001407944.1:c.5063T>C NP_001394873.1:p.Val1688Ala missense NM_001407945.1:c.5063T>C NP_001394874.1:p.Val1688Ala missense NM_001407946.1:c.4874T>C NP_001394875.1:p.Val1625Ala missense NM_001407947.1:c.4874T>C NP_001394876.1:p.Val1625Ala missense NM_001407948.1:c.4874T>C NP_001394877.1:p.Val1625Ala missense NM_001407949.1:c.4874T>C NP_001394878.1:p.Val1625Ala missense NM_001407950.1:c.4871T>C NP_001394879.1:p.Val1624Ala missense NM_001407951.1:c.4871T>C NP_001394880.1:p.Val1624Ala missense NM_001407952.1:c.4871T>C NP_001394881.1:p.Val1624Ala missense NM_001407953.1:c.4871T>C NP_001394882.1:p.Val1624Ala missense NM_001407954.1:c.4871T>C NP_001394883.1:p.Val1624Ala missense NM_001407955.1:c.4871T>C NP_001394884.1:p.Val1624Ala missense NM_001407956.1:c.4868T>C NP_001394885.1:p.Val1623Ala missense NM_001407957.1:c.4868T>C NP_001394886.1:p.Val1623Ala missense NM_001407958.1:c.4868T>C NP_001394887.1:p.Val1623Ala missense NM_001407959.1:c.4826T>C NP_001394888.1:p.Val1609Ala missense NM_001407960.1:c.4823T>C NP_001394889.1:p.Val1608Ala missense NM_001407962.1:c.4823T>C NP_001394891.1:p.Val1608Ala missense NM_001407963.1:c.4820T>C NP_001394892.1:p.Val1607Ala missense NM_001407964.1:c.4745T>C NP_001394893.1:p.Val1582Ala missense NM_001407965.1:c.4700T>C NP_001394894.1:p.Val1567Ala missense NM_001407966.1:c.4319T>C NP_001394895.1:p.Val1440Ala missense NM_001407967.1:c.4316T>C NP_001394896.1:p.Val1439Ala missense NM_001407968.1:c.2603T>C NP_001394897.1:p.Val868Ala missense NM_001407969.1:c.2600T>C NP_001394898.1:p.Val867Ala missense NM_001407970.1:c.1964T>C NP_001394899.1:p.Val655Ala missense NM_001407971.1:c.1964T>C NP_001394900.1:p.Val655Ala missense NM_001407972.1:c.1961T>C NP_001394901.1:p.Val654Ala missense NM_001407973.1:c.1898T>C NP_001394902.1:p.Val633Ala missense NM_001407974.1:c.1898T>C NP_001394903.1:p.Val633Ala missense NM_001407975.1:c.1898T>C NP_001394904.1:p.Val633Ala missense NM_001407976.1:c.1898T>C NP_001394905.1:p.Val633Ala missense NM_001407977.1:c.1898T>C NP_001394906.1:p.Val633Ala missense NM_001407978.1:c.1898T>C NP_001394907.1:p.Val633Ala missense NM_001407979.1:c.1895T>C NP_001394908.1:p.Val632Ala missense NM_001407980.1:c.1895T>C NP_001394909.1:p.Val632Ala missense NM_001407981.1:c.1895T>C NP_001394910.1:p.Val632Ala missense NM_001407982.1:c.1895T>C NP_001394911.1:p.Val632Ala missense NM_001407983.1:c.1895T>C NP_001394912.1:p.Val632Ala missense NM_001407984.1:c.1895T>C NP_001394913.1:p.Val632Ala missense NM_001407985.1:c.1895T>C NP_001394914.1:p.Val632Ala missense NM_001407986.1:c.1895T>C NP_001394915.1:p.Val632Ala missense NM_001407990.1:c.1895T>C NP_001394919.1:p.Val632Ala missense NM_001407991.1:c.1895T>C NP_001394920.1:p.Val632Ala missense NM_001407992.1:c.1895T>C NP_001394921.1:p.Val632Ala missense NM_001407993.1:c.1895T>C NP_001394922.1:p.Val632Ala missense NM_001408392.1:c.1892T>C NP_001395321.1:p.Val631Ala missense NM_001408396.1:c.1892T>C NP_001395325.1:p.Val631Ala missense NM_001408397.1:c.1892T>C NP_001395326.1:p.Val631Ala missense NM_001408398.1:c.1892T>C NP_001395327.1:p.Val631Ala missense NM_001408399.1:c.1892T>C NP_001395328.1:p.Val631Ala missense NM_001408400.1:c.1892T>C NP_001395329.1:p.Val631Ala missense NM_001408401.1:c.1892T>C NP_001395330.1:p.Val631Ala missense NM_001408402.1:c.1892T>C NP_001395331.1:p.Val631Ala missense NM_001408403.1:c.1892T>C NP_001395332.1:p.Val631Ala missense NM_001408404.1:c.1892T>C NP_001395333.1:p.Val631Ala missense NM_001408406.1:c.1889T>C NP_001395335.1:p.Val630Ala missense NM_001408407.1:c.1889T>C NP_001395336.1:p.Val630Ala missense NM_001408408.1:c.1889T>C NP_001395337.1:p.Val630Ala missense NM_001408409.1:c.1886T>C NP_001395338.1:p.Val629Ala missense NM_001408410.1:c.1823T>C NP_001395339.1:p.Val608Ala missense NM_001408411.1:c.1820T>C NP_001395340.1:p.Val607Ala missense NM_001408412.1:c.1817T>C NP_001395341.1:p.Val606Ala missense NM_001408413.1:c.1817T>C NP_001395342.1:p.Val606Ala missense NM_001408414.1:c.1817T>C NP_001395343.1:p.Val606Ala missense NM_001408415.1:c.1817T>C NP_001395344.1:p.Val606Ala missense NM_001408416.1:c.1817T>C NP_001395345.1:p.Val606Ala missense NM_001408418.1:c.1781T>C NP_001395347.1:p.Val594Ala missense NM_001408419.1:c.1781T>C NP_001395348.1:p.Val594Ala missense NM_001408420.1:c.1781T>C NP_001395349.1:p.Val594Ala missense NM_001408421.1:c.1778T>C NP_001395350.1:p.Val593Ala missense NM_001408422.1:c.1778T>C NP_001395351.1:p.Val593Ala missense NM_001408423.1:c.1778T>C NP_001395352.1:p.Val593Ala missense NM_001408424.1:c.1778T>C NP_001395353.1:p.Val593Ala missense NM_001408425.1:c.1775T>C NP_001395354.1:p.Val592Ala missense NM_001408426.1:c.1775T>C NP_001395355.1:p.Val592Ala missense NM_001408427.1:c.1775T>C NP_001395356.1:p.Val592Ala missense NM_001408428.1:c.1775T>C NP_001395357.1:p.Val592Ala missense NM_001408429.1:c.1775T>C NP_001395358.1:p.Val592Ala missense NM_001408430.1:c.1775T>C NP_001395359.1:p.Val592Ala missense NM_001408431.1:c.1775T>C NP_001395360.1:p.Val592Ala missense NM_001408432.1:c.1772T>C NP_001395361.1:p.Val591Ala missense NM_001408433.1:c.1772T>C NP_001395362.1:p.Val591Ala missense NM_001408434.1:c.1772T>C NP_001395363.1:p.Val591Ala missense NM_001408435.1:c.1772T>C NP_001395364.1:p.Val591Ala missense NM_001408436.1:c.1772T>C NP_001395365.1:p.Val591Ala missense NM_001408437.1:c.1772T>C NP_001395366.1:p.Val591Ala missense NM_001408438.1:c.1772T>C NP_001395367.1:p.Val591Ala missense NM_001408439.1:c.1772T>C NP_001395368.1:p.Val591Ala missense NM_001408440.1:c.1772T>C NP_001395369.1:p.Val591Ala missense NM_001408441.1:c.1772T>C NP_001395370.1:p.Val591Ala missense NM_001408442.1:c.1772T>C NP_001395371.1:p.Val591Ala missense NM_001408443.1:c.1772T>C NP_001395372.1:p.Val591Ala missense NM_001408444.1:c.1772T>C NP_001395373.1:p.Val591Ala missense NM_001408445.1:c.1769T>C NP_001395374.1:p.Val590Ala missense NM_001408446.1:c.1769T>C NP_001395375.1:p.Val590Ala missense NM_001408447.1:c.1769T>C NP_001395376.1:p.Val590Ala missense NM_001408448.1:c.1769T>C NP_001395377.1:p.Val590Ala missense NM_001408450.1:c.1769T>C NP_001395379.1:p.Val590Ala missense NM_001408451.1:c.1763T>C NP_001395380.1:p.Val588Ala missense NM_001408452.1:c.1757T>C NP_001395381.1:p.Val586Ala missense NM_001408453.1:c.1757T>C NP_001395382.1:p.Val586Ala missense NM_001408454.1:c.1757T>C NP_001395383.1:p.Val586Ala missense NM_001408455.1:c.1757T>C NP_001395384.1:p.Val586Ala missense NM_001408456.1:c.1757T>C NP_001395385.1:p.Val586Ala missense NM_001408457.1:c.1757T>C NP_001395386.1:p.Val586Ala missense NM_001408458.1:c.1754T>C NP_001395387.1:p.Val585Ala missense NM_001408459.1:c.1754T>C NP_001395388.1:p.Val585Ala missense NM_001408460.1:c.1754T>C NP_001395389.1:p.Val585Ala missense NM_001408461.1:c.1754T>C NP_001395390.1:p.Val585Ala missense NM_001408462.1:c.1754T>C NP_001395391.1:p.Val585Ala missense NM_001408463.1:c.1754T>C NP_001395392.1:p.Val585Ala missense NM_001408464.1:c.1754T>C NP_001395393.1:p.Val585Ala missense NM_001408465.1:c.1754T>C NP_001395394.1:p.Val585Ala missense NM_001408466.1:c.1754T>C NP_001395395.1:p.Val585Ala missense NM_001408467.1:c.1754T>C NP_001395396.1:p.Val585Ala missense NM_001408468.1:c.1751T>C NP_001395397.1:p.Val584Ala missense NM_001408469.1:c.1751T>C NP_001395398.1:p.Val584Ala missense NM_001408470.1:c.1751T>C NP_001395399.1:p.Val584Ala missense NM_001408472.1:c.1895T>C NP_001395401.1:p.Val632Ala missense NM_001408473.1:c.1892T>C NP_001395402.1:p.Val631Ala missense NM_001408474.1:c.1697T>C NP_001395403.1:p.Val566Ala missense NM_001408475.1:c.1694T>C NP_001395404.1:p.Val565Ala missense NM_001408476.1:c.1694T>C NP_001395405.1:p.Val565Ala missense NM_001408478.1:c.1688T>C NP_001395407.1:p.Val563Ala missense NM_001408479.1:c.1688T>C NP_001395408.1:p.Val563Ala missense NM_001408480.1:c.1688T>C NP_001395409.1:p.Val563Ala missense NM_001408481.1:c.1685T>C NP_001395410.1:p.Val562Ala missense NM_001408482.1:c.1685T>C NP_001395411.1:p.Val562Ala missense NM_001408483.1:c.1685T>C NP_001395412.1:p.Val562Ala missense NM_001408484.1:c.1685T>C NP_001395413.1:p.Val562Ala missense NM_001408485.1:c.1685T>C NP_001395414.1:p.Val562Ala missense NM_001408489.1:c.1685T>C NP_001395418.1:p.Val562Ala missense NM_001408490.1:c.1685T>C NP_001395419.1:p.Val562Ala missense NM_001408491.1:c.1685T>C NP_001395420.1:p.Val562Ala missense NM_001408492.1:c.1682T>C NP_001395421.1:p.Val561Ala missense NM_001408493.1:c.1682T>C NP_001395422.1:p.Val561Ala missense NM_001408494.1:c.1658T>C NP_001395423.1:p.Val553Ala missense NM_001408495.1:c.1652T>C NP_001395424.1:p.Val551Ala missense NM_001408496.1:c.1634T>C NP_001395425.1:p.Val545Ala missense NM_001408497.1:c.1634T>C NP_001395426.1:p.Val545Ala missense NM_001408498.1:c.1634T>C NP_001395427.1:p.Val545Ala missense NM_001408499.1:c.1634T>C NP_001395428.1:p.Val545Ala missense NM_001408500.1:c.1634T>C NP_001395429.1:p.Val545Ala missense NM_001408501.1:c.1634T>C NP_001395430.1:p.Val545Ala missense NM_001408502.1:c.1631T>C NP_001395431.1:p.Val544Ala missense NM_001408503.1:c.1631T>C NP_001395432.1:p.Val544Ala missense NM_001408504.1:c.1631T>C NP_001395433.1:p.Val544Ala missense NM_001408505.1:c.1628T>C NP_001395434.1:p.Val543Ala missense NM_001408506.1:c.1571T>C NP_001395435.1:p.Val524Ala missense NM_001408507.1:c.1568T>C NP_001395436.1:p.Val523Ala missense NM_001408508.1:c.1559T>C NP_001395437.1:p.Val520Ala missense NM_001408509.1:c.1556T>C NP_001395438.1:p.Val519Ala missense NM_001408510.1:c.1517T>C NP_001395439.1:p.Val506Ala missense NM_001408511.1:c.1514T>C NP_001395440.1:p.Val505Ala missense NM_001408512.1:c.1394T>C NP_001395441.1:p.Val465Ala missense NM_001408513.1:c.1367T>C NP_001395442.1:p.Val456Ala missense NM_001408514.1:c.971T>C NP_001395443.1:p.Val324Ala missense NM_007297.4:c.5066T>C NP_009228.2:p.Val1689Ala missense NM_007298.4:c.1895T>C NP_009229.2:p.Val632Ala missense NM_007299.4:c.1895T>C NP_009230.2:p.Val632Ala missense NM_007300.4:c.5270T>C NP_009231.2:p.Val1757Ala missense NM_007304.2:c.1895T>C NP_009235.2:p.Val632Ala missense NR_027676.2:n.5384T>C non-coding transcript variant NC_000017.11:g.43057122A>G NC_000017.10:g.41209139A>G NG_005905.2:g.160862T>C LRG_292:g.160862T>C LRG_292t1:c.5207T>C LRG_292p1:p.Val1736Ala P38398:p.Val1736Ala U14680.1:n.5326T>C - Protein change
- V1736A, V1757A, V632A, V1689A, V1567A, V1582A, V1607A, V1624A, V1646A, V1664A, V1668A, V1692A, V1695A, V1716A, V1733A, V1735A, V1756A, V519A, V520A, V545A, V551A, V561A, V562A, V588A, V591A, V593A, V655A, V1439A, V1440A, V1609A, V1623A, V1647A, V1665A, V1669A, V1687A, V1688A, V1693A, V1708A, V324A, V506A, V524A, V543A, V565A, V594A, V606A, V608A, V630A, V631A, V654A, V868A, V1608A, V1666A, V1667A, V1694A, V1709A, V1717A, V1758A, V456A, V465A, V505A, V523A, V544A, V563A, V584A, V629A, V1625A, V1648A, V1710A, V1731A, V1732A, V1734A, V553A, V566A, V585A, V586A, V590A, V592A, V607A, V633A, V867A
- Other names
-
p.V1736A:GTC>GCC
5326T>C
- Canonical SPDI
- NC_000017.11:43057121:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5207T>C, a MISSENSE variant, produced a function score of -1.6, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (9) |
reviewed by expert panel
|
Jun 25, 2019 | RCV000031229.27 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000048857.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 20, 2023 | RCV000131291.22 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV000195366.27 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 2013 | RCV000585878.11 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 25, 2019)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV001161713.2
First in ClinVar: Feb 20, 2020 Last updated: Jan 07, 2023 |
Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based … (more)
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999. (less)
|
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076870.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1736 of the BRCA1 protein (p.Val1736Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1736 of the BRCA1 protein (p.Val1736Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, and/or peritoneal cancer (PMID: 17308087, 23269703). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37648). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20378548, 20516115, 23269703). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Nov 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885080.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Pathogenic
(May 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677660.2
First in ClinVar: May 27, 2015 Last updated: Dec 24, 2022 |
|
|
|
Likely pathogenic
(Aug 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV002819169.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
|
|
|
Pathogenic
(Nov 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296377.5
First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 23269703 (2013), 24240112 (2014), 25452441 (2015), 26219728 (2016), 26786923 (2016), 28283652 (2017), 30055521 (2018)). In addition, a female individual with early onset ovarian cancer and clinical evidence of Fanconi anemia was found to carry this variant and another pathogenic BRCA1 variant in trans (i.e., on opposite chromosomes). Pedigree analysis suggests this variant segregates with disease (PMID: 23269703 (2013)). Functional studies have shown that this variant has a deleterious effect on BRCA1 protein function (PMID: 20516115 (2010), 23269703 (2013), 23867111 (2013), 25748678 (2015), 30209399 (2018), 30765603 (2019), 35196514 (2022)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004817576.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces valine with alanine at codon 1736 in the BRCT1 domain of the BRCA1 protein. Computational prediction tool suggests that this variant … (more)
This missense variant replaces valine with alanine at codon 1736 in the BRCT1 domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes reduced stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 22476429, 23269703, 25452441, 26219728, 26786923). It has been shown that this variant segregates with disease in several individuals from two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004216871.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Jul 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Breast and Ovarian Cancer
Affected status: yes
Allele origin:
germline
|
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV000800820.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Data used in classification: The variant was observed in 6 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing … (more)
Data used in classification: The variant was observed in 6 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (6/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=1.7x10-6 pexact= 8.0x10-5 (PS4_very strong). Seven additional families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA1 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Variant found in trans in individual with a phenotype deemed compatible with Fanconi spectrum, including early onset ovarian cancer and sever chemosensitivity (ref PMID:23269703, Domchek 2013) (PM3). Located in BRCT1 domain (PM1_supp). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv). Impaired function on multiple asssays (ref PMID:23269703, Domchek 2013) (PS3_mod). Segregation reported by Domchek et al (5 meioses). Segregation reported by Ambry (5-9 meioses, not clear if independent from Domchek) (PP1_strong). Comment: The observation of this variant in trans with an established pathogenic variant in the Myriad data set strongly influenced the early classification by ENIGMA of this variant as benign (Easton et al 2007), as it had been believed that biallelic germline mutations in BRCA1 were embryonic lethal. However, since 2007, a number of individuals have been reported with biallelic pathogenic mutations in BRCA1. (less)
Number of individuals with the variant: 6
Sex: female
Geographic origin: United Kingdom
Testing laboratory: UK Molecular Diagnostic Labs
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Pathogenic
(Apr 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715192.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PM2, PM3, PP1_Strong, PP5
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699213.3
First in ClinVar: Dec 26, 2017 Last updated: Jul 10, 2021 |
Comment:
Variant summary: BRCA1 c.5207T>C (p.Val1736Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five … (more)
Variant summary: BRCA1 c.5207T>C (p.Val1736Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 353058 control chromosomes (gnomAD and publications). c.5207T>C has been reported in the literature in individuals affected with a range of cancers including breast, ovarian, fallopian and/or peritoneal cancers (e.g. Carvalho_2007, Domchek_2013, Akbari_2011, Thompson_2016, Shimelis_2017, Judkins_2005, Straub_2018, Arvai_2019). Finch_2016 reports the variant in one AJ proband with Melanoma and Breast cancer as well as a family history of breast cancer under the age of 50. It was reported in a biallelic state with another potentially pathogenic BRCA1 variant (c.2457delC, legacy name: 2576delC) in a proband with early onset papillary serous ovarian carcinoma, microcephaly, and developmental delay with hypersensitivity to chemotherapy (Domchek_2013). The transmission of the co-occurring BRCA1 variant in this family is traceable to the paternal lineage, whereas the variant of interest (c.5207T>C) was transmitted maternally. At least one individual, positive for the c.5207T>C variant in the maternal lineage was reportedly unaffected with any cancer at the age of 51. Additionally, Loss of Heterozygosity (LOH) studies have demonstrated a loss of the wild-type allele in at least 2 of the 5 tumors analyzed in these kindreds. The data as presented precludes unequivocal confirmation of cosegregation of the variant among multiple affected and its absence among unaffected individuals in the families reported. A follow-up correspondence with Dr. Susan Domchek, however, assured us that the analysis was performed on a large number of pedigrees that demonstrated strong cosegregation with disease. At least one report, Akbari_2011, classifies this variant as Benign, citing the report by Easton_2007. However, when taking cosegregation data from Domcheck_2013 into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity 0.999, Vallee_2016). Multiple independent experimental functional studies reporting this variant have demonstrated: 1.) Reduced localization of BRCA1 fragments containing this variant to double stranded breaks (DSB), 2.) Abolished interaction of BRCA1 fragments bearing this variant with RAP80, a BRCT interacting protein, 3) Moderately impaired homology directed DSB repair, 4.) Altered binding to the BRCT phosphopeptide binding domain, and 5.) Markedly decreased transcriptional activity of the mutant BRCA1 constructs. Although it is not clear whether the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Twelve other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at an approximate frequency of 0.03% in our tested population and have followed its classification for 6 years (2014-2020) since its initial identification in a patient tested at our laboratory. In over five years since its initial evaluation, we have not observed any additional evidence supporting a non-pathogenic outcome. Therefore, based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210207.14
First in ClinVar: Feb 24, 2015 Last updated: Aug 31, 2023 |
Comment:
Observed in individuals with breast and/or ovarian cancer, with several studied tumors demonstrating loss of the wild-type allele (Akbari 2011, Hondow 2011, Domchek 2013, Finch … (more)
Observed in individuals with breast and/or ovarian cancer, with several studied tumors demonstrating loss of the wild-type allele (Akbari 2011, Hondow 2011, Domchek 2013, Finch 2016, Schenkel 2016, Thompson 2016); Published functional studies demonstrate a damaging effect: reduced protein stability, homologous recombination activity, transcriptional activation, and cell survival (Carvalho 2007, Karchin 2007, Lee 2010, Domchek 2013, Findlay 2018, Bouwman 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5236T>C; This variant is associated with the following publications: (PMID: 25782689, 23867111, 26884819, 27836010, 26048987, 15172985, 32719484, 32782288, 32546644, 15235020, 21447777, 17308087, 17924331, 26786923, 26219728, 21702907, 21965345, 20378548, 20516115, 25472942, 25748678, 26913838, 27376475, 28283652, 27760710, 27742776, 23580280, 18992264, 15004537, 16677609, 29133208, 29901183, 29435075, 28781887, 29712865, 30209399, 17305420, 30765603, 32123317, 33087888, 35196514, 23269703, 25348405, 28888541, 34308104, 35665744) (less)
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Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242801.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Pathogenic
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683271.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces valine with alanine at codon 1736 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces valine with alanine at codon 1736 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation and a haploid cell proliferation assay (PMID: 29884841, 30209399) and reduces the stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported in several individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 17308087, 22476429, 23269703, 25452441, 26786923, 26219728, 33471991). It has been shown that this variant segregates with disease in two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
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Likely Pathogenic
(Oct 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847833.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Val1736Ala variant in BRCA1 has been identified in at least 5 individuals with BRCA1-associated cancer and segregated with disease in 4 affected relatives, including … (more)
The p.Val1736Ala variant in BRCA1 has been identified in at least 5 individuals with BRCA1-associated cancer and segregated with disease in 4 affected relatives, including 1 obligate carrier (Akbari 2011, Domchek 2013, Finch 2016, Thompson 2016). One of the probands with ovarian cancer, short stature, and developmental delay also carried a loss-of-function variant in BRCA1 in trans (Domchek 2013). This variant was absent from large population studies but has been reported in ClinVar (Variation ID# 37648). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, the majority of in vitro functional studies support a loss-of-function impact on protein function (Carvalho 2007, Lee 2010, Rowling 2010, Domchek 2013, Gaboriau 2015, Woods 2016, Findlay 2018). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PP3, PS4_Supporting. (less)
|
|
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Pathogenic
(Oct 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186262.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.V1736A pathogenic mutation (also known as c.5207T>C), located in coding exon 18 of the BRCA1 gene, results from a T to C substitution at … (more)
The p.V1736A pathogenic mutation (also known as c.5207T>C), located in coding exon 18 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5207. The valine at codon 1736 is replaced by alanine, an amino acid with similar properties. This variant has been detected in trans with a BRCA1 truncating mutation in an individual reported to have clinical features of Fanconi anemia and severe toxicity to chemotherapy (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). The authors also reported the p.V1736A alteration in several other breast and/or ovarian cancer families, and reported that it was found to segregate with disease with a combined odds ratio (OR) of 234:1 in favor of p.V1736A being pathogenic (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). One study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). This variant has also been reported to demonstrate impaired transcriptional activity (Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Fernandes VC et al. J Biol Chem. 2019 Apr;294(15):5980-5992); although in assays of phosphopeptide binding and sensitivity the variant behaved as neutral and intermediate, respectively (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90). Studies of drug response reported the variant as having "unclear" findings with regard to cisplatin sensitivity, but reported the alteration as deleterious based on Olaparib response and HRR activity (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P et al. Clin Cancer Res. 2020 Sep;26(17):4559-4568). Furthermore, several evolutionary and structurally based in silico models predict that p.V1736A is deleterious (Mirkovic N et al. Cancer Res. 2004 Jun;64(11):3790-7; Abkevich VJ. et al. Med. Genet. 2004 Jul;41(7):492-507; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3(2):e26; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev. 2011 Jun;20(6):1078-88). Of note, this alteration is also designated as 5326T>C in published literature. Based on the available evidence, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with features of Fanconi anemia, it may be hypomorphic, and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised. (less)
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Likely pathogenic
(Jun 01, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053829.4
First in ClinVar: Apr 04, 2013 Last updated: May 27, 2015 |
|
|
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Likely pathogenic
(Dec 17, 2015)
|
no assertion criteria provided
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587478.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Apr 01, 2013)
|
no assertion criteria provided
Method: literature only
|
FANCONI ANEMIA, COMPLEMENTATION GROUP S
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000693737.2
First in ClinVar: Mar 11, 2018 Last updated: Mar 25, 2018 |
Comment on evidence:
In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified compound heterozygous mutations … (more)
In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified compound heterozygous mutations in the BRCA1 gene: a c.5207T-C transition, resulting in a val1736-to-ala (V1736A) substitution at a conserved residue, and a 1-bp deletion (c.2457delC; 113705.0039) in exon 11, predicted to result in a frameshift and premature termination (Asp821IlefsTer25). She also carried a heterozygous variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; 604370) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. Tumor tissue from some of the patients with a heterozygous V1736A mutation showed loss of heterozygosity for the wildtype BRCA1 allele, suggesting that the V1736A mutation is pathogenic. Eleven additional pedigrees with BROVCA1 or other types of cancer associated with the V1736A mutation were subsequently ascertained. Segregation analysis yielded a combined odds ratio (OR) of 234:1 in favor of V1736A being pathogenic. In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; 609433) compared to wildtype. No studies of the BRCA2 variant were performed. The paternal line of the proband also had multiple cases of breast cancer, although genetic studies were not performed on most of these individuals. (less)
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Pathogenic
(Apr 01, 2013)
|
no assertion criteria provided
Method: literature only
|
BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000693738.2
First in ClinVar: Mar 17, 2018 Last updated: Mar 25, 2018 |
Comment on evidence:
In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified compound heterozygous mutations … (more)
In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified compound heterozygous mutations in the BRCA1 gene: a c.5207T-C transition, resulting in a val1736-to-ala (V1736A) substitution at a conserved residue, and a 1-bp deletion (c.2457delC; 113705.0039) in exon 11, predicted to result in a frameshift and premature termination (Asp821IlefsTer25). She also carried a heterozygous variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; 604370) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. Tumor tissue from some of the patients with a heterozygous V1736A mutation showed loss of heterozygosity for the wildtype BRCA1 allele, suggesting that the V1736A mutation is pathogenic. Eleven additional pedigrees with BROVCA1 or other types of cancer associated with the V1736A mutation were subsequently ascertained. Segregation analysis yielded a combined odds ratio (OR) of 234:1 in favor of V1736A being pathogenic. In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; 609433) compared to wildtype. No studies of the BRCA2 variant were performed. The paternal line of the proband also had multiple cases of breast cancer, although genetic studies were not performed on most of these individuals. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000591592.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The p.Val1736Ala variant was identified in 13 individuals or families with breast or ovarian cancer (Domchek 2013, Carvalho 2007), and was found by Domchek (2013) … (more)
The p.Val1736Ala variant was identified in 13 individuals or families with breast or ovarian cancer (Domchek 2013, Carvalho 2007), and was found by Domchek (2013) to co-segregate with cancer in multiple families, with a combined odds ratio in favour of p.Val1736Ala being pathogenic of 234:1. Clinical analysis of tumour samples by Domchek (2013) demonstrated loss of the wild-type allele in some tumours; however, Carvalho (2007) found loss of the variant allele in tumour analysis of a proband. The variant listed in dbSNP (ID: rs45553935), HGMD, LOVD, and the BIC database (18 with unknown clinical importance). The variant was classified as pathogenic by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Val1736 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Val1736Ala variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The residue is located in a linker region within the BRCT domain of BRCA1, and the authors of different studies suggest that the p.Val1736Ala variant may affect the stability of the protein and have a long range effect on the binding site (Carvalho 2007, Rowling 2010, Domchek 2013). Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting; however these results are limited. One in silico multifactorial-likelihood ratio model classified this as a neutral variant (Easton 2007). One functional study by Rowling (2010) demonstrated that the variant reduced the binding affinity of phosphopeptides; however, another study by Lee (2010) showed intermediate/strong levels of phosphopeptide interaction. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 3
|
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Uncertain significance
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145392.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 5
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Central/Eastern European
Observation 3:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 4:
Number of individuals with the variant: 9
Ethnicity/Population group: Western European
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, German
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American, Central/Eastern European
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Pathogenic
(Nov 15, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000787909.1
First in ClinVar: May 03, 2018 Last updated: May 03, 2018 |
|
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not provided
(-)
|
no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
|
Brotman Baty Institute, University of Washington
Accession: SCV001242411.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.60309259931805
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Comment:
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1736 of the BRCA1 protein (p.Val1736Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, and/or peritoneal cancer (PMID: 17308087, 23269703). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37648). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20378548, 20516115, 23269703). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 23269703 (2013), 24240112 (2014), 25452441 (2015), 26219728 (2016), 26786923 (2016), 28283652 (2017), 30055521 (2018)). In addition, a female individual with early onset ovarian cancer and clinical evidence of Fanconi anemia was found to carry this variant and another pathogenic BRCA1 variant in trans (i.e., on opposite chromosomes). Pedigree analysis suggests this variant segregates with disease (PMID: 23269703 (2013)). Functional studies have shown that this variant has a deleterious effect on BRCA1 protein function (PMID: 20516115 (2010), 23269703 (2013), 23867111 (2013), 25748678 (2015), 30209399 (2018), 30765603 (2019), 35196514 (2022)). Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces valine with alanine at codon 1736 in the BRCT1 domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes reduced stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 22476429, 23269703, 25452441, 26219728, 26786923). It has been shown that this variant segregates with disease in several individuals from two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Data used in classification: The variant was observed in 6 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (6/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=1.7x10-6 pexact= 8.0x10-5 (PS4_very strong). Seven additional families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA1 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Variant found in trans in individual with a phenotype deemed compatible with Fanconi spectrum, including early onset ovarian cancer and sever chemosensitivity (ref PMID:23269703, Domchek 2013) (PM3). Located in BRCT1 domain (PM1_supp). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv). Impaired function on multiple asssays (ref PMID:23269703, Domchek 2013) (PS3_mod). Segregation reported by Domchek et al (5 meioses). Segregation reported by Ambry (5-9 meioses, not clear if independent from Domchek) (PP1_strong). Comment: The observation of this variant in trans with an established pathogenic variant in the Myriad data set strongly influenced the early classification by ENIGMA of this variant as benign (Easton et al 2007), as it had been believed that biallelic germline mutations in BRCA1 were embryonic lethal. However, since 2007, a number of individuals have been reported with biallelic pathogenic mutations in BRCA1.
Comment:
PS3, PM2, PM3, PP1_Strong, PP5
Comment:
Variant summary: BRCA1 c.5207T>C (p.Val1736Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 353058 control chromosomes (gnomAD and publications). c.5207T>C has been reported in the literature in individuals affected with a range of cancers including breast, ovarian, fallopian and/or peritoneal cancers (e.g. Carvalho_2007, Domchek_2013, Akbari_2011, Thompson_2016, Shimelis_2017, Judkins_2005, Straub_2018, Arvai_2019). Finch_2016 reports the variant in one AJ proband with Melanoma and Breast cancer as well as a family history of breast cancer under the age of 50. It was reported in a biallelic state with another potentially pathogenic BRCA1 variant (c.2457delC, legacy name: 2576delC) in a proband with early onset papillary serous ovarian carcinoma, microcephaly, and developmental delay with hypersensitivity to chemotherapy (Domchek_2013). The transmission of the co-occurring BRCA1 variant in this family is traceable to the paternal lineage, whereas the variant of interest (c.5207T>C) was transmitted maternally. At least one individual, positive for the c.5207T>C variant in the maternal lineage was reportedly unaffected with any cancer at the age of 51. Additionally, Loss of Heterozygosity (LOH) studies have demonstrated a loss of the wild-type allele in at least 2 of the 5 tumors analyzed in these kindreds. The data as presented precludes unequivocal confirmation of cosegregation of the variant among multiple affected and its absence among unaffected individuals in the families reported. A follow-up correspondence with Dr. Susan Domchek, however, assured us that the analysis was performed on a large number of pedigrees that demonstrated strong cosegregation with disease. At least one report, Akbari_2011, classifies this variant as Benign, citing the report by Easton_2007. However, when taking cosegregation data from Domcheck_2013 into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity 0.999, Vallee_2016). Multiple independent experimental functional studies reporting this variant have demonstrated: 1.) Reduced localization of BRCA1 fragments containing this variant to double stranded breaks (DSB), 2.) Abolished interaction of BRCA1 fragments bearing this variant with RAP80, a BRCT interacting protein, 3) Moderately impaired homology directed DSB repair, 4.) Altered binding to the BRCT phosphopeptide binding domain, and 5.) Markedly decreased transcriptional activity of the mutant BRCA1 constructs. Although it is not clear whether the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Twelve other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at an approximate frequency of 0.03% in our tested population and have followed its classification for 6 years (2014-2020) since its initial identification in a patient tested at our laboratory. In over five years since its initial evaluation, we have not observed any additional evidence supporting a non-pathogenic outcome. Therefore, based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Observed in individuals with breast and/or ovarian cancer, with several studied tumors demonstrating loss of the wild-type allele (Akbari 2011, Hondow 2011, Domchek 2013, Finch 2016, Schenkel 2016, Thompson 2016); Published functional studies demonstrate a damaging effect: reduced protein stability, homologous recombination activity, transcriptional activation, and cell survival (Carvalho 2007, Karchin 2007, Lee 2010, Domchek 2013, Findlay 2018, Bouwman 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5236T>C; This variant is associated with the following publications: (PMID: 25782689, 23867111, 26884819, 27836010, 26048987, 15172985, 32719484, 32782288, 32546644, 15235020, 21447777, 17308087, 17924331, 26786923, 26219728, 21702907, 21965345, 20378548, 20516115, 25472942, 25748678, 26913838, 27376475, 28283652, 27760710, 27742776, 23580280, 18992264, 15004537, 16677609, 29133208, 29901183, 29435075, 28781887, 29712865, 30209399, 17305420, 30765603, 32123317, 33087888, 35196514, 23269703, 25348405, 28888541, 34308104, 35665744)
Comment:
This missense variant replaces valine with alanine at codon 1736 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation and a haploid cell proliferation assay (PMID: 29884841, 30209399) and reduces the stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported in several individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 17308087, 22476429, 23269703, 25452441, 26786923, 26219728, 33471991). It has been shown that this variant segregates with disease in two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.Val1736Ala variant in BRCA1 has been identified in at least 5 individuals with BRCA1-associated cancer and segregated with disease in 4 affected relatives, including 1 obligate carrier (Akbari 2011, Domchek 2013, Finch 2016, Thompson 2016). One of the probands with ovarian cancer, short stature, and developmental delay also carried a loss-of-function variant in BRCA1 in trans (Domchek 2013). This variant was absent from large population studies but has been reported in ClinVar (Variation ID# 37648). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, the majority of in vitro functional studies support a loss-of-function impact on protein function (Carvalho 2007, Lee 2010, Rowling 2010, Domchek 2013, Gaboriau 2015, Woods 2016, Findlay 2018). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PP3, PS4_Supporting.
Comment:
The p.V1736A pathogenic mutation (also known as c.5207T>C), located in coding exon 18 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5207. The valine at codon 1736 is replaced by alanine, an amino acid with similar properties. This variant has been detected in trans with a BRCA1 truncating mutation in an individual reported to have clinical features of Fanconi anemia and severe toxicity to chemotherapy (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). The authors also reported the p.V1736A alteration in several other breast and/or ovarian cancer families, and reported that it was found to segregate with disease with a combined odds ratio (OR) of 234:1 in favor of p.V1736A being pathogenic (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). One study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). This variant has also been reported to demonstrate impaired transcriptional activity (Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Fernandes VC et al. J Biol Chem. 2019 Apr;294(15):5980-5992); although in assays of phosphopeptide binding and sensitivity the variant behaved as neutral and intermediate, respectively (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90). Studies of drug response reported the variant as having "unclear" findings with regard to cisplatin sensitivity, but reported the alteration as deleterious based on Olaparib response and HRR activity (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P et al. Clin Cancer Res. 2020 Sep;26(17):4559-4568). Furthermore, several evolutionary and structurally based in silico models predict that p.V1736A is deleterious (Mirkovic N et al. Cancer Res. 2004 Jun;64(11):3790-7; Abkevich VJ. et al. Med. Genet. 2004 Jul;41(7):492-507; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3(2):e26; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev. 2011 Jun;20(6):1078-88). Of note, this alteration is also designated as 5326T>C in published literature. Based on the available evidence, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with features of Fanconi anemia, it may be hypomorphic, and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Comment:
The p.Val1736Ala variant was identified in 13 individuals or families with breast or ovarian cancer (Domchek 2013, Carvalho 2007), and was found by Domchek (2013) to co-segregate with cancer in multiple families, with a combined odds ratio in favour of p.Val1736Ala being pathogenic of 234:1. Clinical analysis of tumour samples by Domchek (2013) demonstrated loss of the wild-type allele in some tumours; however, Carvalho (2007) found loss of the variant allele in tumour analysis of a proband. The variant listed in dbSNP (ID: rs45553935), HGMD, LOVD, and the BIC database (18 with unknown clinical importance). The variant was classified as pathogenic by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Val1736 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Val1736Ala variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The residue is located in a linker region within the BRCT domain of BRCA1, and the authors of different studies suggest that the p.Val1736Ala variant may affect the stability of the protein and have a long range effect on the binding site (Carvalho 2007, Rowling 2010, Domchek 2013). Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting; however these results are limited. One in silico multifactorial-likelihood ratio model classified this as a neutral variant (Easton 2007). One functional study by Rowling (2010) demonstrated that the variant reduced the binding affinity of phosphopeptides; however, another study by Lee (2010) showed intermediate/strong levels of phosphopeptide interaction. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_abnormal
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001242411.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5207T>C, a MISSENSE variant, produced a function score of -1.6, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5207T>C, a MISSENSE variant, produced a function score of -1.6, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
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Comment:
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1736 of the BRCA1 protein (p.Val1736Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, ovarian, and/or peritoneal cancer (PMID: 17308087, 23269703). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37648). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20378548, 20516115, 23269703). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 23269703 (2013), 24240112 (2014), 25452441 (2015), 26219728 (2016), 26786923 (2016), 28283652 (2017), 30055521 (2018)). In addition, a female individual with early onset ovarian cancer and clinical evidence of Fanconi anemia was found to carry this variant and another pathogenic BRCA1 variant in trans (i.e., on opposite chromosomes). Pedigree analysis suggests this variant segregates with disease (PMID: 23269703 (2013)). Functional studies have shown that this variant has a deleterious effect on BRCA1 protein function (PMID: 20516115 (2010), 23269703 (2013), 23867111 (2013), 25748678 (2015), 30209399 (2018), 30765603 (2019), 35196514 (2022)). Based on the available information, this variant is classified as pathogenic.
Comment:
This missense variant replaces valine with alanine at codon 1736 in the BRCT1 domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes reduced stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 22476429, 23269703, 25452441, 26219728, 26786923). It has been shown that this variant segregates with disease in several individuals from two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Data used in classification: The variant was observed in 6 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (6/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=1.7x10-6 pexact= 8.0x10-5 (PS4_very strong). Seven additional families have been identified in the UK (not included in the previous dataset).There are additional reports of this variant in ClinVar, BIC and BRCA1 LOVD. The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on AlignGVGD, SIFT, Polyphen2 HumVar (PP3). Variant found in trans in individual with a phenotype deemed compatible with Fanconi spectrum, including early onset ovarian cancer and sever chemosensitivity (ref PMID:23269703, Domchek 2013) (PM3). Located in BRCT1 domain (PM1_supp). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv). Impaired function on multiple asssays (ref PMID:23269703, Domchek 2013) (PS3_mod). Segregation reported by Domchek et al (5 meioses). Segregation reported by Ambry (5-9 meioses, not clear if independent from Domchek) (PP1_strong). Comment: The observation of this variant in trans with an established pathogenic variant in the Myriad data set strongly influenced the early classification by ENIGMA of this variant as benign (Easton et al 2007), as it had been believed that biallelic germline mutations in BRCA1 were embryonic lethal. However, since 2007, a number of individuals have been reported with biallelic pathogenic mutations in BRCA1.
Comment:
PS3, PM2, PM3, PP1_Strong, PP5
Comment:
Variant summary: BRCA1 c.5207T>C (p.Val1736Ala) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 353058 control chromosomes (gnomAD and publications). c.5207T>C has been reported in the literature in individuals affected with a range of cancers including breast, ovarian, fallopian and/or peritoneal cancers (e.g. Carvalho_2007, Domchek_2013, Akbari_2011, Thompson_2016, Shimelis_2017, Judkins_2005, Straub_2018, Arvai_2019). Finch_2016 reports the variant in one AJ proband with Melanoma and Breast cancer as well as a family history of breast cancer under the age of 50. It was reported in a biallelic state with another potentially pathogenic BRCA1 variant (c.2457delC, legacy name: 2576delC) in a proband with early onset papillary serous ovarian carcinoma, microcephaly, and developmental delay with hypersensitivity to chemotherapy (Domchek_2013). The transmission of the co-occurring BRCA1 variant in this family is traceable to the paternal lineage, whereas the variant of interest (c.5207T>C) was transmitted maternally. At least one individual, positive for the c.5207T>C variant in the maternal lineage was reportedly unaffected with any cancer at the age of 51. Additionally, Loss of Heterozygosity (LOH) studies have demonstrated a loss of the wild-type allele in at least 2 of the 5 tumors analyzed in these kindreds. The data as presented precludes unequivocal confirmation of cosegregation of the variant among multiple affected and its absence among unaffected individuals in the families reported. A follow-up correspondence with Dr. Susan Domchek, however, assured us that the analysis was performed on a large number of pedigrees that demonstrated strong cosegregation with disease. At least one report, Akbari_2011, classifies this variant as Benign, citing the report by Easton_2007. However, when taking cosegregation data from Domcheck_2013 into account, this variant was predicted to be clearly pathogenic (posterior probability of pathogenicity 0.999, Vallee_2016). Multiple independent experimental functional studies reporting this variant have demonstrated: 1.) Reduced localization of BRCA1 fragments containing this variant to double stranded breaks (DSB), 2.) Abolished interaction of BRCA1 fragments bearing this variant with RAP80, a BRCT interacting protein, 3) Moderately impaired homology directed DSB repair, 4.) Altered binding to the BRCT phosphopeptide binding domain, and 5.) Markedly decreased transcriptional activity of the mutant BRCA1 constructs. Although it is not clear whether the results and conclusions drawn from these in-vitro studies are applicable to the mechanism and presentation of disease, the convergence of results obtained from multiple independent functional assays are supportive of a hypomorphic and damaging effect of this variant on the BRCA1 gene product. Twelve other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Some of these submitters provide overlapping evidences utilized in the context of this evaluation. We have observed this variant at an approximate frequency of 0.03% in our tested population and have followed its classification for 6 years (2014-2020) since its initial identification in a patient tested at our laboratory. In over five years since its initial evaluation, we have not observed any additional evidence supporting a non-pathogenic outcome. Therefore, based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Observed in individuals with breast and/or ovarian cancer, with several studied tumors demonstrating loss of the wild-type allele (Akbari 2011, Hondow 2011, Domchek 2013, Finch 2016, Schenkel 2016, Thompson 2016); Published functional studies demonstrate a damaging effect: reduced protein stability, homologous recombination activity, transcriptional activation, and cell survival (Carvalho 2007, Karchin 2007, Lee 2010, Domchek 2013, Findlay 2018, Bouwman 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5236T>C; This variant is associated with the following publications: (PMID: 25782689, 23867111, 26884819, 27836010, 26048987, 15172985, 32719484, 32782288, 32546644, 15235020, 21447777, 17308087, 17924331, 26786923, 26219728, 21702907, 21965345, 20378548, 20516115, 25472942, 25748678, 26913838, 27376475, 28283652, 27760710, 27742776, 23580280, 18992264, 15004537, 16677609, 29133208, 29901183, 29435075, 28781887, 29712865, 30209399, 17305420, 30765603, 32123317, 33087888, 35196514, 23269703, 25348405, 28888541, 34308104, 35665744)
Comment:
This missense variant replaces valine with alanine at codon 1736 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA1 function in transcription activation and a haploid cell proliferation assay (PMID: 29884841, 30209399) and reduces the stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported in several individuals and families affected with breast, ovarian, and peritoneal cancer (PMID: 17308087, 22476429, 23269703, 25452441, 26786923, 26219728, 33471991). It has been shown that this variant segregates with disease in two unrelated families (PMID: 23269703). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.Val1736Ala variant in BRCA1 has been identified in at least 5 individuals with BRCA1-associated cancer and segregated with disease in 4 affected relatives, including 1 obligate carrier (Akbari 2011, Domchek 2013, Finch 2016, Thompson 2016). One of the probands with ovarian cancer, short stature, and developmental delay also carried a loss-of-function variant in BRCA1 in trans (Domchek 2013). This variant was absent from large population studies but has been reported in ClinVar (Variation ID# 37648). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, the majority of in vitro functional studies support a loss-of-function impact on protein function (Carvalho 2007, Lee 2010, Rowling 2010, Domchek 2013, Gaboriau 2015, Woods 2016, Findlay 2018). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PP1, PP3, PS4_Supporting.
Comment:
The p.V1736A pathogenic mutation (also known as c.5207T>C), located in coding exon 18 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5207. The valine at codon 1736 is replaced by alanine, an amino acid with similar properties. This variant has been detected in trans with a BRCA1 truncating mutation in an individual reported to have clinical features of Fanconi anemia and severe toxicity to chemotherapy (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). The authors also reported the p.V1736A alteration in several other breast and/or ovarian cancer families, and reported that it was found to segregate with disease with a combined odds ratio (OR) of 234:1 in favor of p.V1736A being pathogenic (Domchek SM et al. Cancer Discov. 2013 Apr;3(4):399-405). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). One study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 Oct;562(7726):217-222). This variant has also been reported to demonstrate impaired transcriptional activity (Carvalho MA et al. Cancer Res. 2007 Feb;67(4):1494-501; Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Fernandes VC et al. J Biol Chem. 2019 Apr;294(15):5980-5992); although in assays of phosphopeptide binding and sensitivity the variant behaved as neutral and intermediate, respectively (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90). Studies of drug response reported the variant as having "unclear" findings with regard to cisplatin sensitivity, but reported the alteration as deleterious based on Olaparib response and HRR activity (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P et al. Clin Cancer Res. 2020 Sep;26(17):4559-4568). Furthermore, several evolutionary and structurally based in silico models predict that p.V1736A is deleterious (Mirkovic N et al. Cancer Res. 2004 Jun;64(11):3790-7; Abkevich VJ. et al. Med. Genet. 2004 Jul;41(7):492-507; Karchin R et al. PLoS Comput. Biol. 2007 Feb;3(2):e26; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev. 2011 Jun;20(6):1078-88). Of note, this alteration is also designated as 5326T>C in published literature. Based on the available evidence, this alteration is classified as a disease-causing mutation. However, because this variant is identified in one or more patients with features of Fanconi anemia, it may be hypomorphic, and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA1 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Comment:
The p.Val1736Ala variant was identified in 13 individuals or families with breast or ovarian cancer (Domchek 2013, Carvalho 2007), and was found by Domchek (2013) to co-segregate with cancer in multiple families, with a combined odds ratio in favour of p.Val1736Ala being pathogenic of 234:1. Clinical analysis of tumour samples by Domchek (2013) demonstrated loss of the wild-type allele in some tumours; however, Carvalho (2007) found loss of the variant allele in tumour analysis of a proband. The variant listed in dbSNP (ID: rs45553935), HGMD, LOVD, and the BIC database (18 with unknown clinical importance). The variant was classified as pathogenic by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Val1736 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the p.Val1736Ala variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The residue is located in a linker region within the BRCT domain of BRCA1, and the authors of different studies suggest that the p.Val1736Ala variant may affect the stability of the protein and have a long range effect on the binding site (Carvalho 2007, Rowling 2010, Domchek 2013). Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting; however these results are limited. One in silico multifactorial-likelihood ratio model classified this as a neutral variant (Easton 2007). One functional study by Rowling (2010) demonstrated that the variant reduced the binding affinity of phosphopeptides; however, another study by Lee (2010) showed intermediate/strong levels of phosphopeptide interaction. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The functional impact of BRCA1 BRCT domain variants using multiplexed DNA double-strand break repair assays. | Adamovich AI | American journal of human genetics | 2022 | PMID: 35196514 |
| Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study. | Kim J | JNCI cancer spectrum | 2021 | PMID: 34308104 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays. | Bouwman P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2020 | PMID: 32546644 |
| Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia-like phenotype, and no chromosome fragility. | Keupp K | Molecular genetics & genomic medicine | 2019 | PMID: 31347298 |
| Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls. | Arvai KJ | Hereditary cancer in clinical practice | 2019 | PMID: 31341520 |
| Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. | Fernandes VC | The Journal of biological chemistry | 2019 | PMID: 30765603 |
| Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. | Hart SN | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29884841 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Subsequent breast and high grade serous carcinomas after risk-reducing salpingo-oophorectomy in BRCA mutation carriers and patients with history of breast cancer. | Straub MM | Annals of diagnostic pathology | 2018 | PMID: 30055521 |
| Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1. | Seo A | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29712865 |
| BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. | Shimelis H | Cancer research | 2017 | PMID: 28283652 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants. | Vallée MP | Human mutation | 2016 | PMID: 26913838 |
| Panel Testing for Familial Breast Cancer: Calibrating the Tension Between Research and Clinical Care. | Thompson ER | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26786923 |
| Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. | Finch A | Clinical genetics | 2016 | PMID: 26219728 |
| Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. | Vail PJ | Journal of community genetics | 2015 | PMID: 25782689 |
| Protein stability versus function: effects of destabilizing missense mutations on BRCA1 DNA repair activity. | Gaboriau DC | The Biochemical journal | 2015 | PMID: 25748678 |
| Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. | Sawyer SL | Cancer discovery | 2015 | PMID: 25472942 |
| Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
| Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. | Pennington KP | Clinical cancer research : an official journal of the American Association for Cancer Research | 2014 | PMID: 24240112 |
| A high-throughput functional complementation assay for classification of BRCA1 missense variants. | Bouwman P | Cancer discovery | 2013 | PMID: 23867111 |
| BRCA1: a missing link in the Fanconi anemia/BRCA pathway. | D'Andrea AD | Cancer discovery | 2013 | PMID: 23580280 |
| Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. | Domchek SM | Cancer discovery | 2013 | PMID: 23269703 |
| Mutation screening of RAD51C in high-risk breast and ovarian cancer families. | Lu W | Familial cancer | 2012 | PMID: 22476429 |
| Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. | Akbari MR | Journal of medical genetics | 2011 | PMID: 21965345 |
| A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
| A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1. | Iversen ES Jr | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2011 | PMID: 21447777 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| Toward classification of BRCA1 missense variants using a biophysical approach. | Rowling PJ | The Journal of biological chemistry | 2010 | PMID: 20378548 |
| A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. | Easton DF | American journal of human genetics | 2007 | PMID: 17924331 |
| Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. | Carvalho MA | Cancer research | 2007 | PMID: 17308087 |
| Functional impact of missense variants in BRCA1 predicted by supervised learning. | Karchin R | PLoS computational biology | 2007 | PMID: 17305420 |
| Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
| Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. | Mirkovic N | Cancer research | 2004 | PMID: 15172985 |
| Functional characterization of BRCA1 sequence variants using a yeast small colony phenotype assay. | Coyne RS | Cancer biology & therapy | 2004 | PMID: 15004537 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs45553935 ...
HelpThese citations are identified by LitVar using
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Record last updated Nov 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.