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.3929C>A (p.Thr1310Lys)
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.
(14)
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(5); Benign(1); Likely benign(5)
Uncertain significance(5); Benign(1); Likely benign(5)
14
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.3929C>A (p.Thr1310Lys)
Variation ID: 55053 Accession: VCV000055053.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43091602 (GRCh38) [ NCBI UCSC ] 17: 41243619 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 16, 2024 Apr 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.3929C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Thr1310Lys missense NM_001407571.1:c.3716C>A NP_001394500.1:p.Thr1239Lys missense NM_001407581.1:c.3929C>A NP_001394510.1:p.Thr1310Lys missense NM_001407582.1:c.3929C>A NP_001394511.1:p.Thr1310Lys missense NM_001407583.1:c.3929C>A NP_001394512.1:p.Thr1310Lys missense NM_001407585.1:c.3929C>A NP_001394514.1:p.Thr1310Lys missense NM_001407587.1:c.3926C>A NP_001394516.1:p.Thr1309Lys missense NM_001407590.1:c.3926C>A NP_001394519.1:p.Thr1309Lys missense NM_001407591.1:c.3926C>A NP_001394520.1:p.Thr1309Lys missense NM_001407593.1:c.3929C>A NP_001394522.1:p.Thr1310Lys missense NM_001407594.1:c.3929C>A NP_001394523.1:p.Thr1310Lys missense NM_001407596.1:c.3929C>A NP_001394525.1:p.Thr1310Lys missense NM_001407597.1:c.3929C>A NP_001394526.1:p.Thr1310Lys missense NM_001407598.1:c.3929C>A NP_001394527.1:p.Thr1310Lys missense NM_001407602.1:c.3929C>A NP_001394531.1:p.Thr1310Lys missense NM_001407603.1:c.3929C>A NP_001394532.1:p.Thr1310Lys missense NM_001407605.1:c.3929C>A NP_001394534.1:p.Thr1310Lys missense NM_001407610.1:c.3926C>A NP_001394539.1:p.Thr1309Lys missense NM_001407611.1:c.3926C>A NP_001394540.1:p.Thr1309Lys missense NM_001407612.1:c.3926C>A NP_001394541.1:p.Thr1309Lys missense NM_001407613.1:c.3926C>A NP_001394542.1:p.Thr1309Lys missense NM_001407614.1:c.3926C>A NP_001394543.1:p.Thr1309Lys missense NM_001407615.1:c.3926C>A NP_001394544.1:p.Thr1309Lys missense NM_001407616.1:c.3929C>A NP_001394545.1:p.Thr1310Lys missense NM_001407617.1:c.3929C>A NP_001394546.1:p.Thr1310Lys missense NM_001407618.1:c.3929C>A NP_001394547.1:p.Thr1310Lys missense NM_001407619.1:c.3929C>A NP_001394548.1:p.Thr1310Lys missense NM_001407620.1:c.3929C>A NP_001394549.1:p.Thr1310Lys missense NM_001407621.1:c.3929C>A NP_001394550.1:p.Thr1310Lys missense NM_001407622.1:c.3929C>A NP_001394551.1:p.Thr1310Lys missense NM_001407623.1:c.3929C>A NP_001394552.1:p.Thr1310Lys missense NM_001407624.1:c.3929C>A NP_001394553.1:p.Thr1310Lys missense NM_001407625.1:c.3929C>A NP_001394554.1:p.Thr1310Lys missense NM_001407626.1:c.3929C>A NP_001394555.1:p.Thr1310Lys missense NM_001407627.1:c.3926C>A NP_001394556.1:p.Thr1309Lys missense NM_001407628.1:c.3926C>A NP_001394557.1:p.Thr1309Lys missense NM_001407629.1:c.3926C>A NP_001394558.1:p.Thr1309Lys missense NM_001407630.1:c.3926C>A NP_001394559.1:p.Thr1309Lys missense NM_001407631.1:c.3926C>A NP_001394560.1:p.Thr1309Lys missense NM_001407632.1:c.3926C>A NP_001394561.1:p.Thr1309Lys missense NM_001407633.1:c.3926C>A NP_001394562.1:p.Thr1309Lys missense NM_001407634.1:c.3926C>A NP_001394563.1:p.Thr1309Lys missense NM_001407635.1:c.3926C>A NP_001394564.1:p.Thr1309Lys missense NM_001407636.1:c.3926C>A NP_001394565.1:p.Thr1309Lys missense NM_001407637.1:c.3926C>A NP_001394566.1:p.Thr1309Lys missense NM_001407638.1:c.3926C>A NP_001394567.1:p.Thr1309Lys missense NM_001407639.1:c.3929C>A NP_001394568.1:p.Thr1310Lys missense NM_001407640.1:c.3929C>A NP_001394569.1:p.Thr1310Lys missense NM_001407641.1:c.3929C>A NP_001394570.1:p.Thr1310Lys missense NM_001407642.1:c.3929C>A NP_001394571.1:p.Thr1310Lys missense NM_001407644.1:c.3926C>A NP_001394573.1:p.Thr1309Lys missense NM_001407645.1:c.3926C>A NP_001394574.1:p.Thr1309Lys missense NM_001407646.1:c.3920C>A NP_001394575.1:p.Thr1307Lys missense NM_001407647.1:c.3920C>A NP_001394576.1:p.Thr1307Lys missense NM_001407648.1:c.3806C>A NP_001394577.1:p.Thr1269Lys missense NM_001407649.1:c.3803C>A NP_001394578.1:p.Thr1268Lys missense NM_001407652.1:c.3929C>A NP_001394581.1:p.Thr1310Lys missense NM_001407653.1:c.3851C>A NP_001394582.1:p.Thr1284Lys missense NM_001407654.1:c.3851C>A NP_001394583.1:p.Thr1284Lys missense NM_001407655.1:c.3851C>A NP_001394584.1:p.Thr1284Lys missense NM_001407656.1:c.3851C>A NP_001394585.1:p.Thr1284Lys missense NM_001407657.1:c.3851C>A NP_001394586.1:p.Thr1284Lys missense NM_001407658.1:c.3851C>A NP_001394587.1:p.Thr1284Lys missense NM_001407659.1:c.3848C>A NP_001394588.1:p.Thr1283Lys missense NM_001407660.1:c.3848C>A NP_001394589.1:p.Thr1283Lys missense NM_001407661.1:c.3848C>A NP_001394590.1:p.Thr1283Lys missense NM_001407662.1:c.3848C>A NP_001394591.1:p.Thr1283Lys missense NM_001407663.1:c.3851C>A NP_001394592.1:p.Thr1284Lys missense NM_001407664.1:c.3806C>A NP_001394593.1:p.Thr1269Lys missense NM_001407665.1:c.3806C>A NP_001394594.1:p.Thr1269Lys missense NM_001407666.1:c.3806C>A NP_001394595.1:p.Thr1269Lys missense NM_001407667.1:c.3806C>A NP_001394596.1:p.Thr1269Lys missense NM_001407668.1:c.3806C>A NP_001394597.1:p.Thr1269Lys missense NM_001407669.1:c.3806C>A NP_001394598.1:p.Thr1269Lys missense NM_001407670.1:c.3803C>A NP_001394599.1:p.Thr1268Lys missense NM_001407671.1:c.3803C>A NP_001394600.1:p.Thr1268Lys missense NM_001407672.1:c.3803C>A NP_001394601.1:p.Thr1268Lys missense NM_001407673.1:c.3803C>A NP_001394602.1:p.Thr1268Lys missense NM_001407674.1:c.3806C>A NP_001394603.1:p.Thr1269Lys missense NM_001407675.1:c.3806C>A NP_001394604.1:p.Thr1269Lys missense NM_001407676.1:c.3806C>A NP_001394605.1:p.Thr1269Lys missense NM_001407677.1:c.3806C>A NP_001394606.1:p.Thr1269Lys missense NM_001407678.1:c.3806C>A NP_001394607.1:p.Thr1269Lys missense NM_001407679.1:c.3806C>A NP_001394608.1:p.Thr1269Lys missense NM_001407680.1:c.3806C>A NP_001394609.1:p.Thr1269Lys missense NM_001407681.1:c.3806C>A NP_001394610.1:p.Thr1269Lys missense NM_001407682.1:c.3806C>A NP_001394611.1:p.Thr1269Lys missense NM_001407683.1:c.3806C>A NP_001394612.1:p.Thr1269Lys missense NM_001407684.1:c.3929C>A NP_001394613.1:p.Thr1310Lys missense NM_001407685.1:c.3803C>A NP_001394614.1:p.Thr1268Lys missense NM_001407686.1:c.3803C>A NP_001394615.1:p.Thr1268Lys missense NM_001407687.1:c.3803C>A NP_001394616.1:p.Thr1268Lys missense NM_001407688.1:c.3803C>A NP_001394617.1:p.Thr1268Lys missense NM_001407689.1:c.3803C>A NP_001394618.1:p.Thr1268Lys missense NM_001407690.1:c.3803C>A NP_001394619.1:p.Thr1268Lys missense NM_001407691.1:c.3803C>A NP_001394620.1:p.Thr1268Lys missense NM_001407692.1:c.3788C>A NP_001394621.1:p.Thr1263Lys missense NM_001407694.1:c.3788C>A NP_001394623.1:p.Thr1263Lys missense NM_001407695.1:c.3788C>A NP_001394624.1:p.Thr1263Lys missense NM_001407696.1:c.3788C>A NP_001394625.1:p.Thr1263Lys missense NM_001407697.1:c.3788C>A NP_001394626.1:p.Thr1263Lys missense NM_001407698.1:c.3788C>A NP_001394627.1:p.Thr1263Lys missense NM_001407724.1:c.3788C>A NP_001394653.1:p.Thr1263Lys missense NM_001407725.1:c.3788C>A NP_001394654.1:p.Thr1263Lys missense NM_001407726.1:c.3788C>A NP_001394655.1:p.Thr1263Lys missense NM_001407727.1:c.3788C>A NP_001394656.1:p.Thr1263Lys missense NM_001407728.1:c.3788C>A NP_001394657.1:p.Thr1263Lys missense NM_001407729.1:c.3788C>A NP_001394658.1:p.Thr1263Lys missense NM_001407730.1:c.3788C>A NP_001394659.1:p.Thr1263Lys missense NM_001407731.1:c.3788C>A NP_001394660.1:p.Thr1263Lys missense NM_001407732.1:c.3788C>A NP_001394661.1:p.Thr1263Lys missense NM_001407733.1:c.3788C>A NP_001394662.1:p.Thr1263Lys missense NM_001407734.1:c.3788C>A NP_001394663.1:p.Thr1263Lys missense NM_001407735.1:c.3788C>A NP_001394664.1:p.Thr1263Lys missense NM_001407736.1:c.3788C>A NP_001394665.1:p.Thr1263Lys missense NM_001407737.1:c.3788C>A NP_001394666.1:p.Thr1263Lys missense NM_001407738.1:c.3788C>A NP_001394667.1:p.Thr1263Lys missense NM_001407739.1:c.3788C>A NP_001394668.1:p.Thr1263Lys missense NM_001407740.1:c.3785C>A NP_001394669.1:p.Thr1262Lys missense NM_001407741.1:c.3785C>A NP_001394670.1:p.Thr1262Lys missense NM_001407742.1:c.3785C>A NP_001394671.1:p.Thr1262Lys missense NM_001407743.1:c.3785C>A NP_001394672.1:p.Thr1262Lys missense NM_001407744.1:c.3785C>A NP_001394673.1:p.Thr1262Lys missense NM_001407745.1:c.3785C>A NP_001394674.1:p.Thr1262Lys missense NM_001407746.1:c.3785C>A NP_001394675.1:p.Thr1262Lys missense NM_001407747.1:c.3785C>A NP_001394676.1:p.Thr1262Lys missense NM_001407748.1:c.3785C>A NP_001394677.1:p.Thr1262Lys missense NM_001407749.1:c.3785C>A NP_001394678.1:p.Thr1262Lys missense NM_001407750.1:c.3788C>A NP_001394679.1:p.Thr1263Lys missense NM_001407751.1:c.3788C>A NP_001394680.1:p.Thr1263Lys missense NM_001407752.1:c.3788C>A NP_001394681.1:p.Thr1263Lys missense NM_001407838.1:c.3785C>A NP_001394767.1:p.Thr1262Lys missense NM_001407839.1:c.3785C>A NP_001394768.1:p.Thr1262Lys missense NM_001407841.1:c.3785C>A NP_001394770.1:p.Thr1262Lys missense NM_001407842.1:c.3785C>A NP_001394771.1:p.Thr1262Lys missense NM_001407843.1:c.3785C>A NP_001394772.1:p.Thr1262Lys missense NM_001407844.1:c.3785C>A NP_001394773.1:p.Thr1262Lys missense NM_001407845.1:c.3785C>A NP_001394774.1:p.Thr1262Lys missense NM_001407846.1:c.3785C>A NP_001394775.1:p.Thr1262Lys missense NM_001407847.1:c.3785C>A NP_001394776.1:p.Thr1262Lys missense NM_001407848.1:c.3785C>A NP_001394777.1:p.Thr1262Lys missense NM_001407849.1:c.3785C>A NP_001394778.1:p.Thr1262Lys missense NM_001407850.1:c.3788C>A NP_001394779.1:p.Thr1263Lys missense NM_001407851.1:c.3788C>A NP_001394780.1:p.Thr1263Lys missense NM_001407852.1:c.3788C>A NP_001394781.1:p.Thr1263Lys missense NM_001407853.1:c.3716C>A NP_001394782.1:p.Thr1239Lys missense NM_001407854.1:c.3929C>A NP_001394783.1:p.Thr1310Lys missense NM_001407858.1:c.3929C>A NP_001394787.1:p.Thr1310Lys missense NM_001407859.1:c.3929C>A NP_001394788.1:p.Thr1310Lys missense NM_001407860.1:c.3926C>A NP_001394789.1:p.Thr1309Lys missense NM_001407861.1:c.3926C>A NP_001394790.1:p.Thr1309Lys missense NM_001407862.1:c.3728C>A NP_001394791.1:p.Thr1243Lys missense NM_001407863.1:c.3806C>A NP_001394792.1:p.Thr1269Lys missense NM_001407874.1:c.3725C>A NP_001394803.1:p.Thr1242Lys missense NM_001407875.1:c.3725C>A NP_001394804.1:p.Thr1242Lys missense NM_001407879.1:c.3719C>A NP_001394808.1:p.Thr1240Lys missense NM_001407881.1:c.3719C>A NP_001394810.1:p.Thr1240Lys missense NM_001407882.1:c.3719C>A NP_001394811.1:p.Thr1240Lys missense NM_001407884.1:c.3719C>A NP_001394813.1:p.Thr1240Lys missense NM_001407885.1:c.3719C>A NP_001394814.1:p.Thr1240Lys missense NM_001407886.1:c.3719C>A NP_001394815.1:p.Thr1240Lys missense NM_001407887.1:c.3719C>A NP_001394816.1:p.Thr1240Lys missense NM_001407889.1:c.3719C>A NP_001394818.1:p.Thr1240Lys missense NM_001407894.1:c.3716C>A NP_001394823.1:p.Thr1239Lys missense NM_001407895.1:c.3716C>A NP_001394824.1:p.Thr1239Lys missense NM_001407896.1:c.3716C>A NP_001394825.1:p.Thr1239Lys missense NM_001407897.1:c.3716C>A NP_001394826.1:p.Thr1239Lys missense NM_001407898.1:c.3716C>A NP_001394827.1:p.Thr1239Lys missense NM_001407899.1:c.3716C>A NP_001394828.1:p.Thr1239Lys missense NM_001407900.1:c.3719C>A NP_001394829.1:p.Thr1240Lys missense NM_001407902.1:c.3719C>A NP_001394831.1:p.Thr1240Lys missense NM_001407904.1:c.3719C>A NP_001394833.1:p.Thr1240Lys missense NM_001407906.1:c.3719C>A NP_001394835.1:p.Thr1240Lys missense NM_001407907.1:c.3719C>A NP_001394836.1:p.Thr1240Lys missense NM_001407908.1:c.3719C>A NP_001394837.1:p.Thr1240Lys missense NM_001407909.1:c.3719C>A NP_001394838.1:p.Thr1240Lys missense NM_001407910.1:c.3719C>A NP_001394839.1:p.Thr1240Lys missense NM_001407915.1:c.3716C>A NP_001394844.1:p.Thr1239Lys missense NM_001407916.1:c.3716C>A NP_001394845.1:p.Thr1239Lys missense NM_001407917.1:c.3716C>A NP_001394846.1:p.Thr1239Lys missense NM_001407918.1:c.3716C>A NP_001394847.1:p.Thr1239Lys missense NM_001407919.1:c.3806C>A NP_001394848.1:p.Thr1269Lys missense NM_001407920.1:c.3665C>A NP_001394849.1:p.Thr1222Lys missense NM_001407921.1:c.3665C>A NP_001394850.1:p.Thr1222Lys missense NM_001407922.1:c.3665C>A NP_001394851.1:p.Thr1222Lys missense NM_001407923.1:c.3665C>A NP_001394852.1:p.Thr1222Lys missense NM_001407924.1:c.3665C>A NP_001394853.1:p.Thr1222Lys missense NM_001407925.1:c.3665C>A NP_001394854.1:p.Thr1222Lys missense NM_001407926.1:c.3665C>A NP_001394855.1:p.Thr1222Lys missense NM_001407927.1:c.3665C>A NP_001394856.1:p.Thr1222Lys missense NM_001407928.1:c.3665C>A NP_001394857.1:p.Thr1222Lys missense NM_001407929.1:c.3665C>A NP_001394858.1:p.Thr1222Lys missense NM_001407930.1:c.3662C>A NP_001394859.1:p.Thr1221Lys missense NM_001407931.1:c.3662C>A NP_001394860.1:p.Thr1221Lys missense NM_001407932.1:c.3662C>A NP_001394861.1:p.Thr1221Lys missense NM_001407933.1:c.3665C>A NP_001394862.1:p.Thr1222Lys missense NM_001407934.1:c.3662C>A NP_001394863.1:p.Thr1221Lys missense NM_001407935.1:c.3665C>A NP_001394864.1:p.Thr1222Lys missense NM_001407936.1:c.3662C>A NP_001394865.1:p.Thr1221Lys missense NM_001407937.1:c.3806C>A NP_001394866.1:p.Thr1269Lys missense NM_001407938.1:c.3806C>A NP_001394867.1:p.Thr1269Lys missense NM_001407939.1:c.3806C>A NP_001394868.1:p.Thr1269Lys missense NM_001407940.1:c.3803C>A NP_001394869.1:p.Thr1268Lys missense NM_001407941.1:c.3803C>A NP_001394870.1:p.Thr1268Lys missense NM_001407942.1:c.3788C>A NP_001394871.1:p.Thr1263Lys missense NM_001407943.1:c.3785C>A NP_001394872.1:p.Thr1262Lys missense NM_001407944.1:c.3788C>A NP_001394873.1:p.Thr1263Lys missense NM_001407945.1:c.3788C>A NP_001394874.1:p.Thr1263Lys missense NM_001407946.1:c.3596C>A NP_001394875.1:p.Thr1199Lys missense NM_001407947.1:c.3596C>A NP_001394876.1:p.Thr1199Lys missense NM_001407948.1:c.3596C>A NP_001394877.1:p.Thr1199Lys missense NM_001407949.1:c.3596C>A NP_001394878.1:p.Thr1199Lys missense NM_001407950.1:c.3596C>A NP_001394879.1:p.Thr1199Lys missense NM_001407951.1:c.3596C>A NP_001394880.1:p.Thr1199Lys missense NM_001407952.1:c.3596C>A NP_001394881.1:p.Thr1199Lys missense NM_001407953.1:c.3596C>A NP_001394882.1:p.Thr1199Lys missense NM_001407954.1:c.3593C>A NP_001394883.1:p.Thr1198Lys missense NM_001407955.1:c.3593C>A NP_001394884.1:p.Thr1198Lys missense NM_001407956.1:c.3593C>A NP_001394885.1:p.Thr1198Lys missense NM_001407957.1:c.3596C>A NP_001394886.1:p.Thr1199Lys missense NM_001407958.1:c.3593C>A NP_001394887.1:p.Thr1198Lys missense NM_001407959.1:c.3548C>A NP_001394888.1:p.Thr1183Lys missense NM_001407960.1:c.3548C>A NP_001394889.1:p.Thr1183Lys missense NM_001407962.1:c.3545C>A NP_001394891.1:p.Thr1182Lys missense NM_001407963.1:c.3548C>A NP_001394892.1:p.Thr1183Lys missense NM_001407964.1:c.3785C>A NP_001394893.1:p.Thr1262Lys missense NM_001407965.1:c.3425C>A NP_001394894.1:p.Thr1142Lys missense NM_001407966.1:c.3041C>A NP_001394895.1:p.Thr1014Lys missense NM_001407967.1:c.3041C>A NP_001394896.1:p.Thr1014Lys missense NM_001407968.1:c.1325C>A NP_001394897.1:p.Thr442Lys missense NM_001407969.1:c.1325C>A NP_001394898.1:p.Thr442Lys missense NM_001407970.1:c.788-570C>A intron variant NM_001407971.1:c.788-570C>A intron variant NM_001407972.1:c.785-570C>A intron variant NM_001407973.1:c.788-570C>A intron variant NM_001407974.1:c.788-570C>A intron variant NM_001407975.1:c.788-570C>A intron variant NM_001407976.1:c.788-570C>A intron variant NM_001407977.1:c.788-570C>A intron variant NM_001407978.1:c.788-570C>A intron variant NM_001407979.1:c.788-570C>A intron variant NM_001407980.1:c.788-570C>A intron variant NM_001407981.1:c.788-570C>A intron variant NM_001407982.1:c.788-570C>A intron variant NM_001407983.1:c.788-570C>A intron variant NM_001407984.1:c.785-570C>A intron variant NM_001407985.1:c.785-570C>A intron variant NM_001407986.1:c.785-570C>A intron variant NM_001407990.1:c.788-570C>A intron variant NM_001407991.1:c.785-570C>A intron variant NM_001407992.1:c.785-570C>A intron variant NM_001407993.1:c.788-570C>A intron variant NM_001408392.1:c.785-570C>A intron variant NM_001408396.1:c.785-570C>A intron variant NM_001408397.1:c.785-570C>A intron variant NM_001408398.1:c.785-570C>A intron variant NM_001408399.1:c.785-570C>A intron variant NM_001408400.1:c.785-570C>A intron variant NM_001408401.1:c.785-570C>A intron variant NM_001408402.1:c.785-570C>A intron variant NM_001408403.1:c.788-570C>A intron variant NM_001408404.1:c.788-570C>A intron variant NM_001408406.1:c.791-579C>A intron variant NM_001408407.1:c.785-570C>A intron variant NM_001408408.1:c.779-570C>A intron variant NM_001408409.1:c.710-570C>A intron variant NM_001408410.1:c.647-570C>A intron variant NM_001408411.1:c.710-570C>A intron variant NM_001408412.1:c.710-570C>A intron variant NM_001408413.1:c.707-570C>A intron variant NM_001408414.1:c.710-570C>A intron variant NM_001408415.1:c.710-570C>A intron variant NM_001408416.1:c.707-570C>A intron variant NM_001408418.1:c.671-570C>A intron variant NM_001408419.1:c.671-570C>A intron variant NM_001408420.1:c.671-570C>A intron variant NM_001408421.1:c.668-570C>A intron variant NM_001408422.1:c.671-570C>A intron variant NM_001408423.1:c.671-570C>A intron variant NM_001408424.1:c.668-570C>A intron variant NM_001408425.1:c.665-570C>A intron variant NM_001408426.1:c.665-570C>A intron variant NM_001408427.1:c.665-570C>A intron variant NM_001408428.1:c.665-570C>A intron variant NM_001408429.1:c.665-570C>A intron variant NM_001408430.1:c.665-570C>A intron variant NM_001408431.1:c.668-570C>A intron variant NM_001408432.1:c.662-570C>A intron variant NM_001408433.1:c.662-570C>A intron variant NM_001408434.1:c.662-570C>A intron variant NM_001408435.1:c.662-570C>A intron variant NM_001408436.1:c.665-570C>A intron variant NM_001408437.1:c.665-570C>A intron variant NM_001408438.1:c.665-570C>A intron variant NM_001408439.1:c.665-570C>A intron variant NM_001408440.1:c.665-570C>A intron variant NM_001408441.1:c.665-570C>A intron variant NM_001408442.1:c.665-570C>A intron variant NM_001408443.1:c.665-570C>A intron variant NM_001408444.1:c.665-570C>A intron variant NM_001408445.1:c.662-570C>A intron variant NM_001408446.1:c.662-570C>A intron variant NM_001408447.1:c.662-570C>A intron variant NM_001408448.1:c.662-570C>A intron variant NM_001408450.1:c.662-570C>A intron variant NM_001408451.1:c.653-570C>A intron variant NM_001408452.1:c.647-570C>A intron variant NM_001408453.1:c.647-570C>A intron variant NM_001408454.1:c.647-570C>A intron variant NM_001408455.1:c.647-570C>A intron variant NM_001408456.1:c.647-570C>A intron variant NM_001408457.1:c.647-570C>A intron variant NM_001408458.1:c.647-570C>A intron variant NM_001408459.1:c.647-570C>A intron variant NM_001408460.1:c.647-570C>A intron variant NM_001408461.1:c.647-570C>A intron variant NM_001408462.1:c.644-570C>A intron variant NM_001408463.1:c.644-570C>A intron variant NM_001408464.1:c.644-570C>A intron variant NM_001408465.1:c.644-570C>A intron variant NM_001408466.1:c.647-570C>A intron variant NM_001408467.1:c.647-570C>A intron variant NM_001408468.1:c.644-570C>A intron variant NM_001408469.1:c.647-570C>A intron variant NM_001408470.1:c.644-570C>A intron variant NM_001408472.1:c.788-570C>A intron variant NM_001408473.1:c.785-570C>A intron variant NM_001408474.1:c.587-570C>A intron variant NM_001408475.1:c.584-570C>A intron variant NM_001408476.1:c.587-570C>A intron variant NM_001408478.1:c.578-570C>A intron variant NM_001408479.1:c.578-570C>A intron variant NM_001408480.1:c.578-570C>A intron variant NM_001408481.1:c.578-570C>A intron variant NM_001408482.1:c.578-570C>A intron variant NM_001408483.1:c.578-570C>A intron variant NM_001408484.1:c.578-570C>A intron variant NM_001408485.1:c.578-570C>A intron variant NM_001408489.1:c.578-570C>A intron variant NM_001408490.1:c.575-570C>A intron variant NM_001408491.1:c.575-570C>A intron variant NM_001408492.1:c.578-570C>A intron variant NM_001408493.1:c.575-570C>A intron variant NM_001408494.1:c.548-570C>A intron variant NM_001408495.1:c.545-570C>A intron variant NM_001408496.1:c.524-570C>A intron variant NM_001408497.1:c.524-570C>A intron variant NM_001408498.1:c.524-570C>A intron variant NM_001408499.1:c.524-570C>A intron variant NM_001408500.1:c.524-570C>A intron variant NM_001408501.1:c.524-570C>A intron variant NM_001408502.1:c.455-570C>A intron variant NM_001408503.1:c.521-570C>A intron variant NM_001408504.1:c.521-570C>A intron variant NM_001408505.1:c.521-570C>A intron variant NM_001408506.1:c.461-570C>A intron variant NM_001408507.1:c.461-570C>A intron variant NM_001408508.1:c.452-570C>A intron variant NM_001408509.1:c.452-570C>A intron variant NM_001408510.1:c.407-570C>A intron variant NM_001408511.1:c.404-570C>A intron variant NM_001408512.1:c.284-570C>A intron variant NM_001408513.1:c.578-570C>A intron variant NM_001408514.1:c.578-570C>A intron variant NM_007297.4:c.3788C>A NP_009228.2:p.Thr1263Lys missense NM_007298.4:c.788-570C>A intron variant NM_007299.4:c.788-570C>A intron variant NM_007300.4:c.3929C>A NP_009231.2:p.Thr1310Lys missense NR_027676.1:n.4065C>A NC_000017.11:g.43091602G>T NC_000017.10:g.41243619G>T NG_005905.2:g.126382C>A NG_087068.1:g.584G>T LRG_292:g.126382C>A LRG_292t1:c.3929C>A LRG_292p1:p.Thr1310Lys U14680.1:n.4048C>A - Protein change
- T1310K, T1263K, T1142K, T1182K, T1222K, T1239K, T1240K, T1268K, T1283K, T1284K, T1014K, T1307K, T1199K, T1221K, T1309K, T1183K, T1198K, T1242K, T1243K, T1262K, T1269K, T442K
- Other names
-
4048C>A
- Canonical SPDI
- NC_000017.11:43091601:G:T
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00014
The Genome Aggregation Database (gnomAD) 0.00024
- 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 | |
| LOC126862571 | - | - | - | GRCh38 | - | 1651 |
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. |
|---|---|---|---|---|
| Likely benign (1) |
criteria provided, single submitter
|
Jan 21, 2024 | RCV000048383.27 | |
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV000083201.15 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 20, 2023 | RCV000569349.20 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 14, 2020 | RCV000501619.15 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Feb 20, 2024 | RCV000589731.20 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 23, 2024 | RCV003492386.1 | |
| Benign (1) |
criteria provided, single submitter
|
Apr 10, 2024 | RCV003992170.2 |
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 22, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786541.2
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
|
|
|
Likely benign
(Feb 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000605860.3
First in ClinVar: Sep 30, 2017 Last updated: Jan 03, 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: SCV003847732.1
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).
|
|
|
Likely benign
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839243.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(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: SCV000076396.12
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Aug 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000665800.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Uncertain significance
(Aug 14, 2020)
|
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: SCV000699086.2
First in ClinVar: Mar 17, 2018 Last updated: Sep 14, 2020 |
Comment:
Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation … (more)
Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). 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 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
|
|
|
Uncertain significance
(Apr 20, 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: SCV000911049.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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)
|
|
|
Benign
(Apr 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004811983.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Clinical Features:
Breast carcinoma (present)
|
|
|
Uncertain Significance
(May 16, 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: SCV004817725.1
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)
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Comment:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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: 1
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Uncertain significance
(Feb 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209964.9
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Observed in individuals with breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant … (more)
Observed in individuals with breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4048C>A; This variant is associated with the following publications: (PMID: 35980532, 18824701, 15385441, 31131967, 25348012, 33471991, 28717660, 30666157, 15343273, 22737296) (less)
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Uncertain significance
(Jun 20, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144917.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Benign
(May 01, 2012)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
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Sharing Clinical Reports Project (SCRP)
Accession: SCV000115275.3
First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553543.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 1
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Comment:
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). 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 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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 breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4048C>A; This variant is associated with the following publications: (PMID: 35980532, 18824701, 15385441, 31131967, 25348012, 33471991, 28717660, 30666157, 15343273, 22737296)
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:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: BRCA1 c.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). 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 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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:
This missense variant replaces threonine with lysine at codon 1310 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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 breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4048C>A; This variant is associated with the following publications: (PMID: 35980532, 18824701, 15385441, 31131967, 25348012, 33471991, 28717660, 30666157, 15343273, 22737296)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
| Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
| Genetic analysis of subsequent second primary malignant neoplasms in long-term pancreatic cancer survivors suggests new potential hereditary genetic alterations. | Lovecek M | Cancer management and research | 2019 | PMID: 30666157 |
| A novel molecular diagnostics platform for somatic and germline precision oncology. | Cabanillas R | Molecular genetics & genomic medicine | 2017 | PMID: 28717660 |
| Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. | Martelotto LG | Genome biology | 2014 | PMID: 25348012 |
| Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. | Spearman AD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2008 | PMID: 18824701 |
| Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. | Pavlicek A | Human molecular genetics | 2004 | PMID: 15385441 |
| The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs80357257 ...
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 10, 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.