Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.3758C>G (p.Ser1253Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(13)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Uncertain significance(10); Likely benign(1)
Uncertain significance(10); Likely benign(1)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.3758C>G (p.Ser1253Cys)
Variation ID: 186252 Accession: VCV000186252.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q21.31 17: 43091773 (GRCh38) [ NCBI UCSC ] 17: 41243790 (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 Jan 6, 2017 Nov 3, 2024 Oct 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.3758C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Ser1253Cys missense NM_001407571.1:c.3545C>G NP_001394500.1:p.Ser1182Cys missense NM_001407581.1:c.3758C>G NP_001394510.1:p.Ser1253Cys missense NM_001407582.1:c.3758C>G NP_001394511.1:p.Ser1253Cys missense NM_001407583.1:c.3758C>G NP_001394512.1:p.Ser1253Cys missense NM_001407585.1:c.3758C>G NP_001394514.1:p.Ser1253Cys missense NM_001407587.1:c.3755C>G NP_001394516.1:p.Ser1252Cys missense NM_001407590.1:c.3755C>G NP_001394519.1:p.Ser1252Cys missense NM_001407591.1:c.3755C>G NP_001394520.1:p.Ser1252Cys missense NM_001407593.1:c.3758C>G NP_001394522.1:p.Ser1253Cys missense NM_001407594.1:c.3758C>G NP_001394523.1:p.Ser1253Cys missense NM_001407596.1:c.3758C>G NP_001394525.1:p.Ser1253Cys missense NM_001407597.1:c.3758C>G NP_001394526.1:p.Ser1253Cys missense NM_001407598.1:c.3758C>G NP_001394527.1:p.Ser1253Cys missense NM_001407602.1:c.3758C>G NP_001394531.1:p.Ser1253Cys missense NM_001407603.1:c.3758C>G NP_001394532.1:p.Ser1253Cys missense NM_001407605.1:c.3758C>G NP_001394534.1:p.Ser1253Cys missense NM_001407610.1:c.3755C>G NP_001394539.1:p.Ser1252Cys missense NM_001407611.1:c.3755C>G NP_001394540.1:p.Ser1252Cys missense NM_001407612.1:c.3755C>G NP_001394541.1:p.Ser1252Cys missense NM_001407613.1:c.3755C>G NP_001394542.1:p.Ser1252Cys missense NM_001407614.1:c.3755C>G NP_001394543.1:p.Ser1252Cys missense NM_001407615.1:c.3755C>G NP_001394544.1:p.Ser1252Cys missense NM_001407616.1:c.3758C>G NP_001394545.1:p.Ser1253Cys missense NM_001407617.1:c.3758C>G NP_001394546.1:p.Ser1253Cys missense NM_001407618.1:c.3758C>G NP_001394547.1:p.Ser1253Cys missense NM_001407619.1:c.3758C>G NP_001394548.1:p.Ser1253Cys missense NM_001407620.1:c.3758C>G NP_001394549.1:p.Ser1253Cys missense NM_001407621.1:c.3758C>G NP_001394550.1:p.Ser1253Cys missense NM_001407622.1:c.3758C>G NP_001394551.1:p.Ser1253Cys missense NM_001407623.1:c.3758C>G NP_001394552.1:p.Ser1253Cys missense NM_001407624.1:c.3758C>G NP_001394553.1:p.Ser1253Cys missense NM_001407625.1:c.3758C>G NP_001394554.1:p.Ser1253Cys missense NM_001407626.1:c.3758C>G NP_001394555.1:p.Ser1253Cys missense NM_001407627.1:c.3755C>G NP_001394556.1:p.Ser1252Cys missense NM_001407628.1:c.3755C>G NP_001394557.1:p.Ser1252Cys missense NM_001407629.1:c.3755C>G NP_001394558.1:p.Ser1252Cys missense NM_001407630.1:c.3755C>G NP_001394559.1:p.Ser1252Cys missense NM_001407631.1:c.3755C>G NP_001394560.1:p.Ser1252Cys missense NM_001407632.1:c.3755C>G NP_001394561.1:p.Ser1252Cys missense NM_001407633.1:c.3755C>G NP_001394562.1:p.Ser1252Cys missense NM_001407634.1:c.3755C>G NP_001394563.1:p.Ser1252Cys missense NM_001407635.1:c.3755C>G NP_001394564.1:p.Ser1252Cys missense NM_001407636.1:c.3755C>G NP_001394565.1:p.Ser1252Cys missense NM_001407637.1:c.3755C>G NP_001394566.1:p.Ser1252Cys missense NM_001407638.1:c.3755C>G NP_001394567.1:p.Ser1252Cys missense NM_001407639.1:c.3758C>G NP_001394568.1:p.Ser1253Cys missense NM_001407640.1:c.3758C>G NP_001394569.1:p.Ser1253Cys missense NM_001407641.1:c.3758C>G NP_001394570.1:p.Ser1253Cys missense NM_001407642.1:c.3758C>G NP_001394571.1:p.Ser1253Cys missense NM_001407644.1:c.3755C>G NP_001394573.1:p.Ser1252Cys missense NM_001407645.1:c.3755C>G NP_001394574.1:p.Ser1252Cys missense NM_001407646.1:c.3749C>G NP_001394575.1:p.Ser1250Cys missense NM_001407647.1:c.3749C>G NP_001394576.1:p.Ser1250Cys missense NM_001407648.1:c.3635C>G NP_001394577.1:p.Ser1212Cys missense NM_001407649.1:c.3632C>G NP_001394578.1:p.Ser1211Cys missense NM_001407652.1:c.3758C>G NP_001394581.1:p.Ser1253Cys missense NM_001407653.1:c.3680C>G NP_001394582.1:p.Ser1227Cys missense NM_001407654.1:c.3680C>G NP_001394583.1:p.Ser1227Cys missense NM_001407655.1:c.3680C>G NP_001394584.1:p.Ser1227Cys missense NM_001407656.1:c.3680C>G NP_001394585.1:p.Ser1227Cys missense NM_001407657.1:c.3680C>G NP_001394586.1:p.Ser1227Cys missense NM_001407658.1:c.3680C>G NP_001394587.1:p.Ser1227Cys missense NM_001407659.1:c.3677C>G NP_001394588.1:p.Ser1226Cys missense NM_001407660.1:c.3677C>G NP_001394589.1:p.Ser1226Cys missense NM_001407661.1:c.3677C>G NP_001394590.1:p.Ser1226Cys missense NM_001407662.1:c.3677C>G NP_001394591.1:p.Ser1226Cys missense NM_001407663.1:c.3680C>G NP_001394592.1:p.Ser1227Cys missense NM_001407664.1:c.3635C>G NP_001394593.1:p.Ser1212Cys missense NM_001407665.1:c.3635C>G NP_001394594.1:p.Ser1212Cys missense NM_001407666.1:c.3635C>G NP_001394595.1:p.Ser1212Cys missense NM_001407667.1:c.3635C>G NP_001394596.1:p.Ser1212Cys missense NM_001407668.1:c.3635C>G NP_001394597.1:p.Ser1212Cys missense NM_001407669.1:c.3635C>G NP_001394598.1:p.Ser1212Cys missense NM_001407670.1:c.3632C>G NP_001394599.1:p.Ser1211Cys missense NM_001407671.1:c.3632C>G NP_001394600.1:p.Ser1211Cys missense NM_001407672.1:c.3632C>G NP_001394601.1:p.Ser1211Cys missense NM_001407673.1:c.3632C>G NP_001394602.1:p.Ser1211Cys missense NM_001407674.1:c.3635C>G NP_001394603.1:p.Ser1212Cys missense NM_001407675.1:c.3635C>G NP_001394604.1:p.Ser1212Cys missense NM_001407676.1:c.3635C>G NP_001394605.1:p.Ser1212Cys missense NM_001407677.1:c.3635C>G NP_001394606.1:p.Ser1212Cys missense NM_001407678.1:c.3635C>G NP_001394607.1:p.Ser1212Cys missense NM_001407679.1:c.3635C>G NP_001394608.1:p.Ser1212Cys missense NM_001407680.1:c.3635C>G NP_001394609.1:p.Ser1212Cys missense NM_001407681.1:c.3635C>G NP_001394610.1:p.Ser1212Cys missense NM_001407682.1:c.3635C>G NP_001394611.1:p.Ser1212Cys missense NM_001407683.1:c.3635C>G NP_001394612.1:p.Ser1212Cys missense NM_001407684.1:c.3758C>G NP_001394613.1:p.Ser1253Cys missense NM_001407685.1:c.3632C>G NP_001394614.1:p.Ser1211Cys missense NM_001407686.1:c.3632C>G NP_001394615.1:p.Ser1211Cys missense NM_001407687.1:c.3632C>G NP_001394616.1:p.Ser1211Cys missense NM_001407688.1:c.3632C>G NP_001394617.1:p.Ser1211Cys missense NM_001407689.1:c.3632C>G NP_001394618.1:p.Ser1211Cys missense NM_001407690.1:c.3632C>G NP_001394619.1:p.Ser1211Cys missense NM_001407691.1:c.3632C>G NP_001394620.1:p.Ser1211Cys missense NM_001407692.1:c.3617C>G NP_001394621.1:p.Ser1206Cys missense NM_001407694.1:c.3617C>G NP_001394623.1:p.Ser1206Cys missense NM_001407695.1:c.3617C>G NP_001394624.1:p.Ser1206Cys missense NM_001407696.1:c.3617C>G NP_001394625.1:p.Ser1206Cys missense NM_001407697.1:c.3617C>G NP_001394626.1:p.Ser1206Cys missense NM_001407698.1:c.3617C>G NP_001394627.1:p.Ser1206Cys missense NM_001407724.1:c.3617C>G NP_001394653.1:p.Ser1206Cys missense NM_001407725.1:c.3617C>G NP_001394654.1:p.Ser1206Cys missense NM_001407726.1:c.3617C>G NP_001394655.1:p.Ser1206Cys missense NM_001407727.1:c.3617C>G NP_001394656.1:p.Ser1206Cys missense NM_001407728.1:c.3617C>G NP_001394657.1:p.Ser1206Cys missense NM_001407729.1:c.3617C>G NP_001394658.1:p.Ser1206Cys missense NM_001407730.1:c.3617C>G NP_001394659.1:p.Ser1206Cys missense NM_001407731.1:c.3617C>G NP_001394660.1:p.Ser1206Cys missense NM_001407732.1:c.3617C>G NP_001394661.1:p.Ser1206Cys missense NM_001407733.1:c.3617C>G NP_001394662.1:p.Ser1206Cys missense NM_001407734.1:c.3617C>G NP_001394663.1:p.Ser1206Cys missense NM_001407735.1:c.3617C>G NP_001394664.1:p.Ser1206Cys missense NM_001407736.1:c.3617C>G NP_001394665.1:p.Ser1206Cys missense NM_001407737.1:c.3617C>G NP_001394666.1:p.Ser1206Cys missense NM_001407738.1:c.3617C>G NP_001394667.1:p.Ser1206Cys missense NM_001407739.1:c.3617C>G NP_001394668.1:p.Ser1206Cys missense NM_001407740.1:c.3614C>G NP_001394669.1:p.Ser1205Cys missense NM_001407741.1:c.3614C>G NP_001394670.1:p.Ser1205Cys missense NM_001407742.1:c.3614C>G NP_001394671.1:p.Ser1205Cys missense NM_001407743.1:c.3614C>G NP_001394672.1:p.Ser1205Cys missense NM_001407744.1:c.3614C>G NP_001394673.1:p.Ser1205Cys missense NM_001407745.1:c.3614C>G NP_001394674.1:p.Ser1205Cys missense NM_001407746.1:c.3614C>G NP_001394675.1:p.Ser1205Cys missense NM_001407747.1:c.3614C>G NP_001394676.1:p.Ser1205Cys missense NM_001407748.1:c.3614C>G NP_001394677.1:p.Ser1205Cys missense NM_001407749.1:c.3614C>G NP_001394678.1:p.Ser1205Cys missense NM_001407750.1:c.3617C>G NP_001394679.1:p.Ser1206Cys missense NM_001407751.1:c.3617C>G NP_001394680.1:p.Ser1206Cys missense NM_001407752.1:c.3617C>G NP_001394681.1:p.Ser1206Cys missense NM_001407838.1:c.3614C>G NP_001394767.1:p.Ser1205Cys missense NM_001407839.1:c.3614C>G NP_001394768.1:p.Ser1205Cys missense NM_001407841.1:c.3614C>G NP_001394770.1:p.Ser1205Cys missense NM_001407842.1:c.3614C>G NP_001394771.1:p.Ser1205Cys missense NM_001407843.1:c.3614C>G NP_001394772.1:p.Ser1205Cys missense NM_001407844.1:c.3614C>G NP_001394773.1:p.Ser1205Cys missense NM_001407845.1:c.3614C>G NP_001394774.1:p.Ser1205Cys missense NM_001407846.1:c.3614C>G NP_001394775.1:p.Ser1205Cys missense NM_001407847.1:c.3614C>G NP_001394776.1:p.Ser1205Cys missense NM_001407848.1:c.3614C>G NP_001394777.1:p.Ser1205Cys missense NM_001407849.1:c.3614C>G NP_001394778.1:p.Ser1205Cys missense NM_001407850.1:c.3617C>G NP_001394779.1:p.Ser1206Cys missense NM_001407851.1:c.3617C>G NP_001394780.1:p.Ser1206Cys missense NM_001407852.1:c.3617C>G NP_001394781.1:p.Ser1206Cys missense NM_001407853.1:c.3545C>G NP_001394782.1:p.Ser1182Cys missense NM_001407854.1:c.3758C>G NP_001394783.1:p.Ser1253Cys missense NM_001407858.1:c.3758C>G NP_001394787.1:p.Ser1253Cys missense NM_001407859.1:c.3758C>G NP_001394788.1:p.Ser1253Cys missense NM_001407860.1:c.3755C>G NP_001394789.1:p.Ser1252Cys missense NM_001407861.1:c.3755C>G NP_001394790.1:p.Ser1252Cys missense NM_001407862.1:c.3557C>G NP_001394791.1:p.Ser1186Cys missense NM_001407863.1:c.3635C>G NP_001394792.1:p.Ser1212Cys missense NM_001407874.1:c.3554C>G NP_001394803.1:p.Ser1185Cys missense NM_001407875.1:c.3554C>G NP_001394804.1:p.Ser1185Cys missense NM_001407879.1:c.3548C>G NP_001394808.1:p.Ser1183Cys missense NM_001407881.1:c.3548C>G NP_001394810.1:p.Ser1183Cys missense NM_001407882.1:c.3548C>G NP_001394811.1:p.Ser1183Cys missense NM_001407884.1:c.3548C>G NP_001394813.1:p.Ser1183Cys missense NM_001407885.1:c.3548C>G NP_001394814.1:p.Ser1183Cys missense NM_001407886.1:c.3548C>G NP_001394815.1:p.Ser1183Cys missense NM_001407887.1:c.3548C>G NP_001394816.1:p.Ser1183Cys missense NM_001407889.1:c.3548C>G NP_001394818.1:p.Ser1183Cys missense NM_001407894.1:c.3545C>G NP_001394823.1:p.Ser1182Cys missense NM_001407895.1:c.3545C>G NP_001394824.1:p.Ser1182Cys missense NM_001407896.1:c.3545C>G NP_001394825.1:p.Ser1182Cys missense NM_001407897.1:c.3545C>G NP_001394826.1:p.Ser1182Cys missense NM_001407898.1:c.3545C>G NP_001394827.1:p.Ser1182Cys missense NM_001407899.1:c.3545C>G NP_001394828.1:p.Ser1182Cys missense NM_001407900.1:c.3548C>G NP_001394829.1:p.Ser1183Cys missense NM_001407902.1:c.3548C>G NP_001394831.1:p.Ser1183Cys missense NM_001407904.1:c.3548C>G NP_001394833.1:p.Ser1183Cys missense NM_001407906.1:c.3548C>G NP_001394835.1:p.Ser1183Cys missense NM_001407907.1:c.3548C>G NP_001394836.1:p.Ser1183Cys missense NM_001407908.1:c.3548C>G NP_001394837.1:p.Ser1183Cys missense NM_001407909.1:c.3548C>G NP_001394838.1:p.Ser1183Cys missense NM_001407910.1:c.3548C>G NP_001394839.1:p.Ser1183Cys missense NM_001407915.1:c.3545C>G NP_001394844.1:p.Ser1182Cys missense NM_001407916.1:c.3545C>G NP_001394845.1:p.Ser1182Cys missense NM_001407917.1:c.3545C>G NP_001394846.1:p.Ser1182Cys missense NM_001407918.1:c.3545C>G NP_001394847.1:p.Ser1182Cys missense NM_001407919.1:c.3635C>G NP_001394848.1:p.Ser1212Cys missense NM_001407920.1:c.3494C>G NP_001394849.1:p.Ser1165Cys missense NM_001407921.1:c.3494C>G NP_001394850.1:p.Ser1165Cys missense NM_001407922.1:c.3494C>G NP_001394851.1:p.Ser1165Cys missense NM_001407923.1:c.3494C>G NP_001394852.1:p.Ser1165Cys missense NM_001407924.1:c.3494C>G NP_001394853.1:p.Ser1165Cys missense NM_001407925.1:c.3494C>G NP_001394854.1:p.Ser1165Cys missense NM_001407926.1:c.3494C>G NP_001394855.1:p.Ser1165Cys missense NM_001407927.1:c.3494C>G NP_001394856.1:p.Ser1165Cys missense NM_001407928.1:c.3494C>G NP_001394857.1:p.Ser1165Cys missense NM_001407929.1:c.3494C>G NP_001394858.1:p.Ser1165Cys missense NM_001407930.1:c.3491C>G NP_001394859.1:p.Ser1164Cys missense NM_001407931.1:c.3491C>G NP_001394860.1:p.Ser1164Cys missense NM_001407932.1:c.3491C>G NP_001394861.1:p.Ser1164Cys missense NM_001407933.1:c.3494C>G NP_001394862.1:p.Ser1165Cys missense NM_001407934.1:c.3491C>G NP_001394863.1:p.Ser1164Cys missense NM_001407935.1:c.3494C>G NP_001394864.1:p.Ser1165Cys missense NM_001407936.1:c.3491C>G NP_001394865.1:p.Ser1164Cys missense NM_001407937.1:c.3635C>G NP_001394866.1:p.Ser1212Cys missense NM_001407938.1:c.3635C>G NP_001394867.1:p.Ser1212Cys missense NM_001407939.1:c.3635C>G NP_001394868.1:p.Ser1212Cys missense NM_001407940.1:c.3632C>G NP_001394869.1:p.Ser1211Cys missense NM_001407941.1:c.3632C>G NP_001394870.1:p.Ser1211Cys missense NM_001407942.1:c.3617C>G NP_001394871.1:p.Ser1206Cys missense NM_001407943.1:c.3614C>G NP_001394872.1:p.Ser1205Cys missense NM_001407944.1:c.3617C>G NP_001394873.1:p.Ser1206Cys missense NM_001407945.1:c.3617C>G NP_001394874.1:p.Ser1206Cys missense NM_001407946.1:c.3425C>G NP_001394875.1:p.Ser1142Cys missense NM_001407947.1:c.3425C>G NP_001394876.1:p.Ser1142Cys missense NM_001407948.1:c.3425C>G NP_001394877.1:p.Ser1142Cys missense NM_001407949.1:c.3425C>G NP_001394878.1:p.Ser1142Cys missense NM_001407950.1:c.3425C>G NP_001394879.1:p.Ser1142Cys missense NM_001407951.1:c.3425C>G NP_001394880.1:p.Ser1142Cys missense NM_001407952.1:c.3425C>G NP_001394881.1:p.Ser1142Cys missense NM_001407953.1:c.3425C>G NP_001394882.1:p.Ser1142Cys missense NM_001407954.1:c.3422C>G NP_001394883.1:p.Ser1141Cys missense NM_001407955.1:c.3422C>G NP_001394884.1:p.Ser1141Cys missense NM_001407956.1:c.3422C>G NP_001394885.1:p.Ser1141Cys missense NM_001407957.1:c.3425C>G NP_001394886.1:p.Ser1142Cys missense NM_001407958.1:c.3422C>G NP_001394887.1:p.Ser1141Cys missense NM_001407959.1:c.3377C>G NP_001394888.1:p.Ser1126Cys missense NM_001407960.1:c.3377C>G NP_001394889.1:p.Ser1126Cys missense NM_001407962.1:c.3374C>G NP_001394891.1:p.Ser1125Cys missense NM_001407963.1:c.3377C>G NP_001394892.1:p.Ser1126Cys missense NM_001407964.1:c.3614C>G NP_001394893.1:p.Ser1205Cys missense NM_001407965.1:c.3254C>G NP_001394894.1:p.Ser1085Cys missense NM_001407966.1:c.2870C>G NP_001394895.1:p.Ser957Cys missense NM_001407967.1:c.2870C>G NP_001394896.1:p.Ser957Cys missense NM_001407968.1:c.1154C>G NP_001394897.1:p.Ser385Cys missense NM_001407969.1:c.1154C>G NP_001394898.1:p.Ser385Cys missense NM_001407970.1:c.788-741C>G intron variant NM_001407971.1:c.788-741C>G intron variant NM_001407972.1:c.785-741C>G intron variant NM_001407973.1:c.788-741C>G intron variant NM_001407974.1:c.788-741C>G intron variant NM_001407975.1:c.788-741C>G intron variant NM_001407976.1:c.788-741C>G intron variant NM_001407977.1:c.788-741C>G intron variant NM_001407978.1:c.788-741C>G intron variant NM_001407979.1:c.788-741C>G intron variant NM_001407980.1:c.788-741C>G intron variant NM_001407981.1:c.788-741C>G intron variant NM_001407982.1:c.788-741C>G intron variant NM_001407983.1:c.788-741C>G intron variant NM_001407984.1:c.785-741C>G intron variant NM_001407985.1:c.785-741C>G intron variant NM_001407986.1:c.785-741C>G intron variant NM_001407990.1:c.788-741C>G intron variant NM_001407991.1:c.785-741C>G intron variant NM_001407992.1:c.785-741C>G intron variant NM_001407993.1:c.788-741C>G intron variant NM_001408392.1:c.785-741C>G intron variant NM_001408396.1:c.785-741C>G intron variant NM_001408397.1:c.785-741C>G intron variant NM_001408398.1:c.785-741C>G intron variant NM_001408399.1:c.785-741C>G intron variant NM_001408400.1:c.785-741C>G intron variant NM_001408401.1:c.785-741C>G intron variant NM_001408402.1:c.785-741C>G intron variant NM_001408403.1:c.788-741C>G intron variant NM_001408404.1:c.788-741C>G intron variant NM_001408406.1:c.791-750C>G intron variant NM_001408407.1:c.785-741C>G intron variant NM_001408408.1:c.779-741C>G intron variant NM_001408409.1:c.710-741C>G intron variant NM_001408410.1:c.647-741C>G intron variant NM_001408411.1:c.710-741C>G intron variant NM_001408412.1:c.710-741C>G intron variant NM_001408413.1:c.707-741C>G intron variant NM_001408414.1:c.710-741C>G intron variant NM_001408415.1:c.710-741C>G intron variant NM_001408416.1:c.707-741C>G intron variant NM_001408418.1:c.671-741C>G intron variant NM_001408419.1:c.671-741C>G intron variant NM_001408420.1:c.671-741C>G intron variant NM_001408421.1:c.668-741C>G intron variant NM_001408422.1:c.671-741C>G intron variant NM_001408423.1:c.671-741C>G intron variant NM_001408424.1:c.668-741C>G intron variant NM_001408425.1:c.665-741C>G intron variant NM_001408426.1:c.665-741C>G intron variant NM_001408427.1:c.665-741C>G intron variant NM_001408428.1:c.665-741C>G intron variant NM_001408429.1:c.665-741C>G intron variant NM_001408430.1:c.665-741C>G intron variant NM_001408431.1:c.668-741C>G intron variant NM_001408432.1:c.662-741C>G intron variant NM_001408433.1:c.662-741C>G intron variant NM_001408434.1:c.662-741C>G intron variant NM_001408435.1:c.662-741C>G intron variant NM_001408436.1:c.665-741C>G intron variant NM_001408437.1:c.665-741C>G intron variant NM_001408438.1:c.665-741C>G intron variant NM_001408439.1:c.665-741C>G intron variant NM_001408440.1:c.665-741C>G intron variant NM_001408441.1:c.665-741C>G intron variant NM_001408442.1:c.665-741C>G intron variant NM_001408443.1:c.665-741C>G intron variant NM_001408444.1:c.665-741C>G intron variant NM_001408445.1:c.662-741C>G intron variant NM_001408446.1:c.662-741C>G intron variant NM_001408447.1:c.662-741C>G intron variant NM_001408448.1:c.662-741C>G intron variant NM_001408450.1:c.662-741C>G intron variant NM_001408451.1:c.653-741C>G intron variant NM_001408452.1:c.647-741C>G intron variant NM_001408453.1:c.647-741C>G intron variant NM_001408454.1:c.647-741C>G intron variant NM_001408455.1:c.647-741C>G intron variant NM_001408456.1:c.647-741C>G intron variant NM_001408457.1:c.647-741C>G intron variant NM_001408458.1:c.647-741C>G intron variant NM_001408459.1:c.647-741C>G intron variant NM_001408460.1:c.647-741C>G intron variant NM_001408461.1:c.647-741C>G intron variant NM_001408462.1:c.644-741C>G intron variant NM_001408463.1:c.644-741C>G intron variant NM_001408464.1:c.644-741C>G intron variant NM_001408465.1:c.644-741C>G intron variant NM_001408466.1:c.647-741C>G intron variant NM_001408467.1:c.647-741C>G intron variant NM_001408468.1:c.644-741C>G intron variant NM_001408469.1:c.647-741C>G intron variant NM_001408470.1:c.644-741C>G intron variant NM_001408472.1:c.788-741C>G intron variant NM_001408473.1:c.785-741C>G intron variant NM_001408474.1:c.587-741C>G intron variant NM_001408475.1:c.584-741C>G intron variant NM_001408476.1:c.587-741C>G intron variant NM_001408478.1:c.578-741C>G intron variant NM_001408479.1:c.578-741C>G intron variant NM_001408480.1:c.578-741C>G intron variant NM_001408481.1:c.578-741C>G intron variant NM_001408482.1:c.578-741C>G intron variant NM_001408483.1:c.578-741C>G intron variant NM_001408484.1:c.578-741C>G intron variant NM_001408485.1:c.578-741C>G intron variant NM_001408489.1:c.578-741C>G intron variant NM_001408490.1:c.575-741C>G intron variant NM_001408491.1:c.575-741C>G intron variant NM_001408492.1:c.578-741C>G intron variant NM_001408493.1:c.575-741C>G intron variant NM_001408494.1:c.548-741C>G intron variant NM_001408495.1:c.545-741C>G intron variant NM_001408496.1:c.524-741C>G intron variant NM_001408497.1:c.524-741C>G intron variant NM_001408498.1:c.524-741C>G intron variant NM_001408499.1:c.524-741C>G intron variant NM_001408500.1:c.524-741C>G intron variant NM_001408501.1:c.524-741C>G intron variant NM_001408502.1:c.455-741C>G intron variant NM_001408503.1:c.521-741C>G intron variant NM_001408504.1:c.521-741C>G intron variant NM_001408505.1:c.521-741C>G intron variant NM_001408506.1:c.461-741C>G intron variant NM_001408507.1:c.461-741C>G intron variant NM_001408508.1:c.452-741C>G intron variant NM_001408509.1:c.452-741C>G intron variant NM_001408510.1:c.407-741C>G intron variant NM_001408511.1:c.404-741C>G intron variant NM_001408512.1:c.284-741C>G intron variant NM_001408513.1:c.578-741C>G intron variant NM_001408514.1:c.578-741C>G intron variant NM_007297.4:c.3617C>G NP_009228.2:p.Ser1206Cys missense NM_007298.4:c.788-741C>G intron variant NM_007299.4:c.788-741C>G intron variant NM_007300.4:c.3758C>G NP_009231.2:p.Ser1253Cys missense NR_027676.1:n.3894C>G NC_000017.11:g.43091773G>C NC_000017.10:g.41243790G>C NG_005905.2:g.126211C>G NG_087068.1:g.755G>C LRG_292:g.126211C>G LRG_292t1:c.3758C>G LRG_292p1:p.Ser1253Cys - Protein change
- S1253C, S1206C, S1085C, S1125C, S1141C, S1183C, S1211C, S1226C, S1164C, S1165C, S1205C, S1227C, S1250C, S1252C, S385C, S1126C, S1142C, S1182C, S1185C, S1186C, S1212C, S957C
- Other names
- -
- Canonical SPDI
- NC_000017.11:43091772:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- 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 |
13051 | 14858 | |
| LOC126862571 | - | - | - | GRCh38 | - | 1652 |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 5, 2023 | RCV000165814.17 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Jan 18, 2024 | RCV000203862.14 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 30, 2023 | RCV000411367.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2024 | RCV000759525.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 31, 2018 | RCV001170594.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 15, 2022 | RCV001193747.3 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001354503.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 4, 2021 | RCV002485026.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333182.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
|
Uncertain significance
(Jul 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488895.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003848117.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA1 coldspot (exon 11 using historical exon numbering). Reclassification based on statistical prior probability
|
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
|
Uncertain significance
(Jul 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888896.4
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 32885271 (2021), 25036526 (2014)). In a large-scale breast … (more)
In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 32885271 (2021), 25036526 (2014)). In a large-scale breast cancer association study, this variant was observed in a breast cancer case and in a control individual (see LOVD (http://databases.lovd.nl/shared/genes/BRCA1) and PMID: 33471991 (2021)). In addition, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000039 (5/128986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Sep 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000683131.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Aug 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000216561.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.S1253C variant (also known as c.3758C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide … (more)
The p.S1253C variant (also known as c.3758C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3758. The serine at codon 1253 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported in an individual with ovarian cancer (Gleicher N et al. PLoS ONE. 2014 Jul;9:e102370). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Jul 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362816.2
First in ClinVar: Jun 22, 2020 Last updated: Sep 17, 2022 |
Comment:
Variant summary: BRCA1 c.3758C>G (p.Ser1253Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: BRCA1 c.3758C>G (p.Ser1253Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758C>G has been reported in the literature in at least one individual affected with Ovarian Cancer (example, Gleicher_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Aug 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Breast-ovarian cancer, familial, susceptibility to, 1 Pancreatic cancer, susceptibility to, 4 Fanconi anemia, complementation group S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002788774.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Jan 18, 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: SCV000260312.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1253 of the BRCA1 protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1253 of the BRCA1 protein (p.Ser1253Cys). This variant is present in population databases (rs397509100, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 25036526, 34326862). ClinVar contains an entry for this variant (Variation ID: 186252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain Significance
(Nov 30, 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: SCV004817752.1
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 serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(Oct 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000564736.6
First in ClinVar: Apr 29, 2017 Last updated: Nov 03, 2024 |
Comment:
Observed in individuals with ovarian cancer and breast cancer in published literature (PMID: 25036526, 34326862, 33471991, 32885271); Not observed at significant frequency in large population … (more)
Observed in individuals with ovarian cancer and breast cancer in published literature (PMID: 25036526, 34326862, 33471991, 32885271); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3877C>G; This variant is associated with the following publications: (PMID: 28726806, 31642931, 33471991, 25036526, 34326862, 32885271) (less)
|
|
|
Uncertain significance
(Apr 18, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000586895.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
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: SCV001549139.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Ser1253Cys variant was identified in 2 of 172 proband chromosomes (frequency: 0.01) from Austrian individuals or families with ovarian cancer (Gleicher 2014); these … (more)
The BRCA1 p.Ser1253Cys variant was identified in 2 of 172 proband chromosomes (frequency: 0.01) from Austrian individuals or families with ovarian cancer (Gleicher 2014); these two patients had co-occurring, unclassified BRCA2 variants. The variant was identified in dbSNP (ID: rs397509100) “With Uncertain significance, untested allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, and GeneDx). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was also identified in control databases in 5 of 276974 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the European Non-Finnish population in 5 of 126476 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1253 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Cys variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 32885271 (2021), 25036526 (2014)). In a large-scale breast cancer association study, this variant was observed in a breast cancer case and in a control individual (see LOVD (http://databases.lovd.nl/shared/genes/BRCA1) and PMID: 33471991 (2021)). In addition, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000039 (5/128986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S1253C variant (also known as c.3758C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3758. The serine at codon 1253 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported in an individual with ovarian cancer (Gleicher N et al. PLoS ONE. 2014 Jul;9:e102370). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: BRCA1 c.3758C>G (p.Ser1253Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758C>G has been reported in the literature in at least one individual affected with Ovarian Cancer (example, Gleicher_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1253 of the BRCA1 protein (p.Ser1253Cys). This variant is present in population databases (rs397509100, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 25036526, 34326862). ClinVar contains an entry for this variant (Variation ID: 186252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Observed in individuals with ovarian cancer and breast cancer in published literature (PMID: 25036526, 34326862, 33471991, 32885271); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3877C>G; This variant is associated with the following publications: (PMID: 28726806, 31642931, 33471991, 25036526, 34326862, 32885271)
Comment:
The BRCA1 p.Ser1253Cys variant was identified in 2 of 172 proband chromosomes (frequency: 0.01) from Austrian individuals or families with ovarian cancer (Gleicher 2014); these two patients had co-occurring, unclassified BRCA2 variants. The variant was identified in dbSNP (ID: rs397509100) “With Uncertain significance, untested allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, and GeneDx). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was also identified in control databases in 5 of 276974 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the European Non-Finnish population in 5 of 126476 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1253 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Cys variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Comment:
In the published literature, this variant has been reported in individuals with breast or ovarian cancer (PMIDs: 32885271 (2021), 25036526 (2014)). In a large-scale breast cancer association study, this variant was observed in a breast cancer case and in a control individual (see LOVD (http://databases.lovd.nl/shared/genes/BRCA1) and PMID: 33471991 (2021)). In addition, this variant has been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000039 (5/128986 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S1253C variant (also known as c.3758C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3758. The serine at codon 1253 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been reported in an individual with ovarian cancer (Gleicher N et al. PLoS ONE. 2014 Jul;9:e102370). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Variant summary: BRCA1 c.3758C>G (p.Ser1253Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3758C>G has been reported in the literature in at least one individual affected with Ovarian Cancer (example, Gleicher_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1253 of the BRCA1 protein (p.Ser1253Cys). This variant is present in population databases (rs397509100, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 25036526, 34326862). ClinVar contains an entry for this variant (Variation ID: 186252). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant replaces serine with cysteine at codon 1253 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with ovarian cancer (PMID: 25036526) and in a breast cancer case-control meta-analysis in 1/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006306). This variant also has been detected in an individual age 70 years or older without cancer (FLOSSIES database). This variant has been identified in 5/282660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Observed in individuals with ovarian cancer and breast cancer in published literature (PMID: 25036526, 34326862, 33471991, 32885271); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3877C>G; This variant is associated with the following publications: (PMID: 28726806, 31642931, 33471991, 25036526, 34326862, 32885271)
Comment:
The BRCA1 p.Ser1253Cys variant was identified in 2 of 172 proband chromosomes (frequency: 0.01) from Austrian individuals or families with ovarian cancer (Gleicher 2014); these two patients had co-occurring, unclassified BRCA2 variants. The variant was identified in dbSNP (ID: rs397509100) “With Uncertain significance, untested allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, and GeneDx). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was also identified in control databases in 5 of 276974 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), observed in the European Non-Finnish population in 5 of 126476 chromosomes (freq: 0.00004), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser1253 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Cys variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
| 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 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
| Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. | Karam R | JAMA network open | 2019 | PMID: 31642931 |
| Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR). | Lebo MS | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726806 |
| Absence of BRCA/FMR1 correlations in women with ovarian cancers. | Gleicher N | PloS one | 2014 | PMID: 25036526 |
Text-mined citations for rs397509100 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.