Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4524G>A (p.Trp1508Ter)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Sep 2016 by
Evidence-based…
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.4524G>A (p.Trp1508Ter)
Variation ID: 55221 Accession: VCV000055221.75
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43074482 (GRCh38) [ NCBI UCSC ] 17: 41226499 (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 Jul 7, 2024 Sep 8, 2016 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4524G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Trp1508Ter nonsense NM_001407571.1:c.4311G>A NP_001394500.1:p.Trp1437Ter nonsense NM_001407581.1:c.4590G>A NP_001394510.1:p.Trp1530Ter nonsense NM_001407582.1:c.4590G>A NP_001394511.1:p.Trp1530Ter nonsense NM_001407583.1:c.4587G>A NP_001394512.1:p.Trp1529Ter nonsense NM_001407585.1:c.4587G>A NP_001394514.1:p.Trp1529Ter nonsense NM_001407587.1:c.4587G>A NP_001394516.1:p.Trp1529Ter nonsense NM_001407590.1:c.4584G>A NP_001394519.1:p.Trp1528Ter nonsense NM_001407591.1:c.4584G>A NP_001394520.1:p.Trp1528Ter nonsense NM_001407593.1:c.4524G>A NP_001394522.1:p.Trp1508Ter nonsense NM_001407594.1:c.4524G>A NP_001394523.1:p.Trp1508Ter nonsense NM_001407596.1:c.4524G>A NP_001394525.1:p.Trp1508Ter nonsense NM_001407597.1:c.4524G>A NP_001394526.1:p.Trp1508Ter nonsense NM_001407598.1:c.4524G>A NP_001394527.1:p.Trp1508Ter nonsense NM_001407602.1:c.4524G>A NP_001394531.1:p.Trp1508Ter nonsense NM_001407603.1:c.4524G>A NP_001394532.1:p.Trp1508Ter nonsense NM_001407605.1:c.4524G>A NP_001394534.1:p.Trp1508Ter nonsense NM_001407610.1:c.4521G>A NP_001394539.1:p.Trp1507Ter nonsense NM_001407611.1:c.4521G>A NP_001394540.1:p.Trp1507Ter nonsense NM_001407612.1:c.4521G>A NP_001394541.1:p.Trp1507Ter nonsense NM_001407613.1:c.4521G>A NP_001394542.1:p.Trp1507Ter nonsense NM_001407614.1:c.4521G>A NP_001394543.1:p.Trp1507Ter nonsense NM_001407615.1:c.4521G>A NP_001394544.1:p.Trp1507Ter nonsense NM_001407616.1:c.4521G>A NP_001394545.1:p.Trp1507Ter nonsense NM_001407617.1:c.4521G>A NP_001394546.1:p.Trp1507Ter nonsense NM_001407618.1:c.4521G>A NP_001394547.1:p.Trp1507Ter nonsense NM_001407619.1:c.4521G>A NP_001394548.1:p.Trp1507Ter nonsense NM_001407620.1:c.4521G>A NP_001394549.1:p.Trp1507Ter nonsense NM_001407621.1:c.4521G>A NP_001394550.1:p.Trp1507Ter nonsense NM_001407622.1:c.4521G>A NP_001394551.1:p.Trp1507Ter nonsense NM_001407623.1:c.4521G>A NP_001394552.1:p.Trp1507Ter nonsense NM_001407624.1:c.4521G>A NP_001394553.1:p.Trp1507Ter nonsense NM_001407625.1:c.4521G>A NP_001394554.1:p.Trp1507Ter nonsense NM_001407626.1:c.4521G>A NP_001394555.1:p.Trp1507Ter nonsense NM_001407627.1:c.4518G>A NP_001394556.1:p.Trp1506Ter nonsense NM_001407628.1:c.4518G>A NP_001394557.1:p.Trp1506Ter nonsense NM_001407629.1:c.4518G>A NP_001394558.1:p.Trp1506Ter nonsense NM_001407630.1:c.4518G>A NP_001394559.1:p.Trp1506Ter nonsense NM_001407631.1:c.4518G>A NP_001394560.1:p.Trp1506Ter nonsense NM_001407632.1:c.4518G>A NP_001394561.1:p.Trp1506Ter nonsense NM_001407633.1:c.4518G>A NP_001394562.1:p.Trp1506Ter nonsense NM_001407634.1:c.4518G>A NP_001394563.1:p.Trp1506Ter nonsense NM_001407635.1:c.4518G>A NP_001394564.1:p.Trp1506Ter nonsense NM_001407636.1:c.4518G>A NP_001394565.1:p.Trp1506Ter nonsense NM_001407637.1:c.4518G>A NP_001394566.1:p.Trp1506Ter nonsense NM_001407638.1:c.4518G>A NP_001394567.1:p.Trp1506Ter nonsense NM_001407639.1:c.4518G>A NP_001394568.1:p.Trp1506Ter nonsense NM_001407640.1:c.4518G>A NP_001394569.1:p.Trp1506Ter nonsense NM_001407641.1:c.4518G>A NP_001394570.1:p.Trp1506Ter nonsense NM_001407642.1:c.4518G>A NP_001394571.1:p.Trp1506Ter nonsense NM_001407644.1:c.4515G>A NP_001394573.1:p.Trp1505Ter nonsense NM_001407645.1:c.4515G>A NP_001394574.1:p.Trp1505Ter nonsense NM_001407646.1:c.4512G>A NP_001394575.1:p.Trp1504Ter nonsense NM_001407647.1:c.4509G>A NP_001394576.1:p.Trp1503Ter nonsense NM_001407648.1:c.4467G>A NP_001394577.1:p.Trp1489Ter nonsense NM_001407649.1:c.4464G>A NP_001394578.1:p.Trp1488Ter nonsense NM_001407652.1:c.4524G>A NP_001394581.1:p.Trp1508Ter nonsense NM_001407653.1:c.4446G>A NP_001394582.1:p.Trp1482Ter nonsense NM_001407654.1:c.4446G>A NP_001394583.1:p.Trp1482Ter nonsense NM_001407655.1:c.4446G>A NP_001394584.1:p.Trp1482Ter nonsense NM_001407656.1:c.4443G>A NP_001394585.1:p.Trp1481Ter nonsense NM_001407657.1:c.4443G>A NP_001394586.1:p.Trp1481Ter nonsense NM_001407658.1:c.4443G>A NP_001394587.1:p.Trp1481Ter nonsense NM_001407659.1:c.4440G>A NP_001394588.1:p.Trp1480Ter nonsense NM_001407660.1:c.4440G>A NP_001394589.1:p.Trp1480Ter nonsense NM_001407661.1:c.4440G>A NP_001394590.1:p.Trp1480Ter nonsense NM_001407662.1:c.4440G>A NP_001394591.1:p.Trp1480Ter nonsense NM_001407663.1:c.4440G>A NP_001394592.1:p.Trp1480Ter nonsense NM_001407664.1:c.4401G>A NP_001394593.1:p.Trp1467Ter nonsense NM_001407665.1:c.4401G>A NP_001394594.1:p.Trp1467Ter nonsense NM_001407666.1:c.4401G>A NP_001394595.1:p.Trp1467Ter nonsense NM_001407667.1:c.4401G>A NP_001394596.1:p.Trp1467Ter nonsense NM_001407668.1:c.4401G>A NP_001394597.1:p.Trp1467Ter nonsense NM_001407669.1:c.4401G>A NP_001394598.1:p.Trp1467Ter nonsense NM_001407670.1:c.4398G>A NP_001394599.1:p.Trp1466Ter nonsense NM_001407671.1:c.4398G>A NP_001394600.1:p.Trp1466Ter nonsense NM_001407672.1:c.4398G>A NP_001394601.1:p.Trp1466Ter nonsense NM_001407673.1:c.4398G>A NP_001394602.1:p.Trp1466Ter nonsense NM_001407674.1:c.4398G>A NP_001394603.1:p.Trp1466Ter nonsense NM_001407675.1:c.4398G>A NP_001394604.1:p.Trp1466Ter nonsense NM_001407676.1:c.4398G>A NP_001394605.1:p.Trp1466Ter nonsense NM_001407677.1:c.4398G>A NP_001394606.1:p.Trp1466Ter nonsense NM_001407678.1:c.4398G>A NP_001394607.1:p.Trp1466Ter nonsense NM_001407679.1:c.4398G>A NP_001394608.1:p.Trp1466Ter nonsense NM_001407680.1:c.4398G>A NP_001394609.1:p.Trp1466Ter nonsense NM_001407681.1:c.4395G>A NP_001394610.1:p.Trp1465Ter nonsense NM_001407682.1:c.4395G>A NP_001394611.1:p.Trp1465Ter nonsense NM_001407683.1:c.4395G>A NP_001394612.1:p.Trp1465Ter nonsense NM_001407684.1:c.4524G>A NP_001394613.1:p.Trp1508Ter nonsense NM_001407685.1:c.4395G>A NP_001394614.1:p.Trp1465Ter nonsense NM_001407686.1:c.4395G>A NP_001394615.1:p.Trp1465Ter nonsense NM_001407687.1:c.4395G>A NP_001394616.1:p.Trp1465Ter nonsense NM_001407688.1:c.4395G>A NP_001394617.1:p.Trp1465Ter nonsense NM_001407689.1:c.4395G>A NP_001394618.1:p.Trp1465Ter nonsense NM_001407690.1:c.4392G>A NP_001394619.1:p.Trp1464Ter nonsense NM_001407691.1:c.4392G>A NP_001394620.1:p.Trp1464Ter nonsense NM_001407692.1:c.4383G>A NP_001394621.1:p.Trp1461Ter nonsense NM_001407694.1:c.4383G>A NP_001394623.1:p.Trp1461Ter nonsense NM_001407695.1:c.4383G>A NP_001394624.1:p.Trp1461Ter nonsense NM_001407696.1:c.4383G>A NP_001394625.1:p.Trp1461Ter nonsense NM_001407697.1:c.4383G>A NP_001394626.1:p.Trp1461Ter nonsense NM_001407698.1:c.4383G>A NP_001394627.1:p.Trp1461Ter nonsense NM_001407724.1:c.4383G>A NP_001394653.1:p.Trp1461Ter nonsense NM_001407725.1:c.4383G>A NP_001394654.1:p.Trp1461Ter nonsense NM_001407726.1:c.4383G>A NP_001394655.1:p.Trp1461Ter nonsense NM_001407727.1:c.4383G>A NP_001394656.1:p.Trp1461Ter nonsense NM_001407728.1:c.4383G>A NP_001394657.1:p.Trp1461Ter nonsense NM_001407729.1:c.4383G>A NP_001394658.1:p.Trp1461Ter nonsense NM_001407730.1:c.4383G>A NP_001394659.1:p.Trp1461Ter nonsense NM_001407731.1:c.4383G>A NP_001394660.1:p.Trp1461Ter nonsense NM_001407732.1:c.4380G>A NP_001394661.1:p.Trp1460Ter nonsense NM_001407733.1:c.4380G>A NP_001394662.1:p.Trp1460Ter nonsense NM_001407734.1:c.4380G>A NP_001394663.1:p.Trp1460Ter nonsense NM_001407735.1:c.4380G>A NP_001394664.1:p.Trp1460Ter nonsense NM_001407736.1:c.4380G>A NP_001394665.1:p.Trp1460Ter nonsense NM_001407737.1:c.4380G>A NP_001394666.1:p.Trp1460Ter nonsense NM_001407738.1:c.4380G>A NP_001394667.1:p.Trp1460Ter nonsense NM_001407739.1:c.4380G>A NP_001394668.1:p.Trp1460Ter nonsense NM_001407740.1:c.4380G>A NP_001394669.1:p.Trp1460Ter nonsense NM_001407741.1:c.4380G>A NP_001394670.1:p.Trp1460Ter nonsense NM_001407742.1:c.4380G>A NP_001394671.1:p.Trp1460Ter nonsense NM_001407743.1:c.4380G>A NP_001394672.1:p.Trp1460Ter nonsense NM_001407744.1:c.4380G>A NP_001394673.1:p.Trp1460Ter nonsense NM_001407745.1:c.4380G>A NP_001394674.1:p.Trp1460Ter nonsense NM_001407746.1:c.4380G>A NP_001394675.1:p.Trp1460Ter nonsense NM_001407747.1:c.4380G>A NP_001394676.1:p.Trp1460Ter nonsense NM_001407748.1:c.4380G>A NP_001394677.1:p.Trp1460Ter nonsense NM_001407749.1:c.4380G>A NP_001394678.1:p.Trp1460Ter nonsense NM_001407750.1:c.4380G>A NP_001394679.1:p.Trp1460Ter nonsense NM_001407751.1:c.4380G>A NP_001394680.1:p.Trp1460Ter nonsense NM_001407752.1:c.4380G>A NP_001394681.1:p.Trp1460Ter nonsense NM_001407838.1:c.4377G>A NP_001394767.1:p.Trp1459Ter nonsense NM_001407839.1:c.4377G>A NP_001394768.1:p.Trp1459Ter nonsense NM_001407841.1:c.4377G>A NP_001394770.1:p.Trp1459Ter nonsense NM_001407842.1:c.4377G>A NP_001394771.1:p.Trp1459Ter nonsense NM_001407843.1:c.4377G>A NP_001394772.1:p.Trp1459Ter nonsense NM_001407844.1:c.4377G>A NP_001394773.1:p.Trp1459Ter nonsense NM_001407845.1:c.4377G>A NP_001394774.1:p.Trp1459Ter nonsense NM_001407846.1:c.4377G>A NP_001394775.1:p.Trp1459Ter nonsense NM_001407847.1:c.4377G>A NP_001394776.1:p.Trp1459Ter nonsense NM_001407848.1:c.4377G>A NP_001394777.1:p.Trp1459Ter nonsense NM_001407849.1:c.4377G>A NP_001394778.1:p.Trp1459Ter nonsense NM_001407850.1:c.4377G>A NP_001394779.1:p.Trp1459Ter nonsense NM_001407851.1:c.4377G>A NP_001394780.1:p.Trp1459Ter nonsense NM_001407852.1:c.4377G>A NP_001394781.1:p.Trp1459Ter nonsense NM_001407853.1:c.4377G>A NP_001394782.1:p.Trp1459Ter nonsense NM_001407854.1:c.4524G>A NP_001394783.1:p.Trp1508Ter nonsense NM_001407858.1:c.4521G>A NP_001394787.1:p.Trp1507Ter nonsense NM_001407859.1:c.4521G>A NP_001394788.1:p.Trp1507Ter nonsense NM_001407860.1:c.4521G>A NP_001394789.1:p.Trp1507Ter nonsense NM_001407861.1:c.4518G>A NP_001394790.1:p.Trp1506Ter nonsense NM_001407862.1:c.4323G>A NP_001394791.1:p.Trp1441Ter nonsense NM_001407863.1:c.4398G>A NP_001394792.1:p.Trp1466Ter nonsense NM_001407874.1:c.4317G>A NP_001394803.1:p.Trp1439Ter nonsense NM_001407875.1:c.4317G>A NP_001394804.1:p.Trp1439Ter nonsense NM_001407879.1:c.4314G>A NP_001394808.1:p.Trp1438Ter nonsense NM_001407881.1:c.4314G>A NP_001394810.1:p.Trp1438Ter nonsense NM_001407882.1:c.4314G>A NP_001394811.1:p.Trp1438Ter nonsense NM_001407884.1:c.4314G>A NP_001394813.1:p.Trp1438Ter nonsense NM_001407885.1:c.4314G>A NP_001394814.1:p.Trp1438Ter nonsense NM_001407886.1:c.4314G>A NP_001394815.1:p.Trp1438Ter nonsense NM_001407887.1:c.4314G>A NP_001394816.1:p.Trp1438Ter nonsense NM_001407889.1:c.4314G>A NP_001394818.1:p.Trp1438Ter nonsense NM_001407894.1:c.4311G>A NP_001394823.1:p.Trp1437Ter nonsense NM_001407895.1:c.4311G>A NP_001394824.1:p.Trp1437Ter nonsense NM_001407896.1:c.4311G>A NP_001394825.1:p.Trp1437Ter nonsense NM_001407897.1:c.4311G>A NP_001394826.1:p.Trp1437Ter nonsense NM_001407898.1:c.4311G>A NP_001394827.1:p.Trp1437Ter nonsense NM_001407899.1:c.4311G>A NP_001394828.1:p.Trp1437Ter nonsense NM_001407900.1:c.4311G>A NP_001394829.1:p.Trp1437Ter nonsense NM_001407902.1:c.4311G>A NP_001394831.1:p.Trp1437Ter nonsense NM_001407904.1:c.4311G>A NP_001394833.1:p.Trp1437Ter nonsense NM_001407906.1:c.4311G>A NP_001394835.1:p.Trp1437Ter nonsense NM_001407907.1:c.4311G>A NP_001394836.1:p.Trp1437Ter nonsense NM_001407908.1:c.4311G>A NP_001394837.1:p.Trp1437Ter nonsense NM_001407909.1:c.4311G>A NP_001394838.1:p.Trp1437Ter nonsense NM_001407910.1:c.4311G>A NP_001394839.1:p.Trp1437Ter nonsense NM_001407915.1:c.4308G>A NP_001394844.1:p.Trp1436Ter nonsense NM_001407916.1:c.4308G>A NP_001394845.1:p.Trp1436Ter nonsense NM_001407917.1:c.4308G>A NP_001394846.1:p.Trp1436Ter nonsense NM_001407918.1:c.4308G>A NP_001394847.1:p.Trp1436Ter nonsense NM_001407919.1:c.4401G>A NP_001394848.1:p.Trp1467Ter nonsense NM_001407920.1:c.4260G>A NP_001394849.1:p.Trp1420Ter nonsense NM_001407921.1:c.4260G>A NP_001394850.1:p.Trp1420Ter nonsense NM_001407922.1:c.4260G>A NP_001394851.1:p.Trp1420Ter nonsense NM_001407923.1:c.4260G>A NP_001394852.1:p.Trp1420Ter nonsense NM_001407924.1:c.4260G>A NP_001394853.1:p.Trp1420Ter nonsense NM_001407925.1:c.4260G>A NP_001394854.1:p.Trp1420Ter nonsense NM_001407926.1:c.4260G>A NP_001394855.1:p.Trp1420Ter nonsense NM_001407927.1:c.4257G>A NP_001394856.1:p.Trp1419Ter nonsense NM_001407928.1:c.4257G>A NP_001394857.1:p.Trp1419Ter nonsense NM_001407929.1:c.4257G>A NP_001394858.1:p.Trp1419Ter nonsense NM_001407930.1:c.4257G>A NP_001394859.1:p.Trp1419Ter nonsense NM_001407931.1:c.4257G>A NP_001394860.1:p.Trp1419Ter nonsense NM_001407932.1:c.4257G>A NP_001394861.1:p.Trp1419Ter nonsense NM_001407933.1:c.4257G>A NP_001394862.1:p.Trp1419Ter nonsense NM_001407934.1:c.4254G>A NP_001394863.1:p.Trp1418Ter nonsense NM_001407935.1:c.4254G>A NP_001394864.1:p.Trp1418Ter nonsense NM_001407936.1:c.4254G>A NP_001394865.1:p.Trp1418Ter nonsense NM_001407937.1:c.4401G>A NP_001394866.1:p.Trp1467Ter nonsense NM_001407938.1:c.4401G>A NP_001394867.1:p.Trp1467Ter nonsense NM_001407939.1:c.4398G>A NP_001394868.1:p.Trp1466Ter nonsense NM_001407940.1:c.4398G>A NP_001394869.1:p.Trp1466Ter nonsense NM_001407941.1:c.4395G>A NP_001394870.1:p.Trp1465Ter nonsense NM_001407942.1:c.4383G>A NP_001394871.1:p.Trp1461Ter nonsense NM_001407943.1:c.4380G>A NP_001394872.1:p.Trp1460Ter nonsense NM_001407944.1:c.4380G>A NP_001394873.1:p.Trp1460Ter nonsense NM_001407945.1:c.4380G>A NP_001394874.1:p.Trp1460Ter nonsense NM_001407946.1:c.4191G>A NP_001394875.1:p.Trp1397Ter nonsense NM_001407947.1:c.4191G>A NP_001394876.1:p.Trp1397Ter nonsense NM_001407948.1:c.4191G>A NP_001394877.1:p.Trp1397Ter nonsense NM_001407949.1:c.4191G>A NP_001394878.1:p.Trp1397Ter nonsense NM_001407950.1:c.4188G>A NP_001394879.1:p.Trp1396Ter nonsense NM_001407951.1:c.4188G>A NP_001394880.1:p.Trp1396Ter nonsense NM_001407952.1:c.4188G>A NP_001394881.1:p.Trp1396Ter nonsense NM_001407953.1:c.4188G>A NP_001394882.1:p.Trp1396Ter nonsense NM_001407954.1:c.4188G>A NP_001394883.1:p.Trp1396Ter nonsense NM_001407955.1:c.4188G>A NP_001394884.1:p.Trp1396Ter nonsense NM_001407956.1:c.4185G>A NP_001394885.1:p.Trp1395Ter nonsense NM_001407957.1:c.4185G>A NP_001394886.1:p.Trp1395Ter nonsense NM_001407958.1:c.4185G>A NP_001394887.1:p.Trp1395Ter nonsense NM_001407959.1:c.4143G>A NP_001394888.1:p.Trp1381Ter nonsense NM_001407960.1:c.4140G>A NP_001394889.1:p.Trp1380Ter nonsense NM_001407962.1:c.4140G>A NP_001394891.1:p.Trp1380Ter nonsense NM_001407963.1:c.4137G>A NP_001394892.1:p.Trp1379Ter nonsense NM_001407965.1:c.4017G>A NP_001394894.1:p.Trp1339Ter nonsense NM_001407966.1:c.3636G>A NP_001394895.1:p.Trp1212Ter nonsense NM_001407967.1:c.3633G>A NP_001394896.1:p.Trp1211Ter nonsense NM_001407968.1:c.1920G>A NP_001394897.1:p.Trp640Ter nonsense NM_001407969.1:c.1917G>A NP_001394898.1:p.Trp639Ter nonsense NM_001407970.1:c.1281G>A NP_001394899.1:p.Trp427Ter nonsense NM_001407971.1:c.1281G>A NP_001394900.1:p.Trp427Ter nonsense NM_001407972.1:c.1278G>A NP_001394901.1:p.Trp426Ter nonsense NM_001407973.1:c.1215G>A NP_001394902.1:p.Trp405Ter nonsense NM_001407974.1:c.1215G>A NP_001394903.1:p.Trp405Ter nonsense NM_001407975.1:c.1215G>A NP_001394904.1:p.Trp405Ter nonsense NM_001407976.1:c.1215G>A NP_001394905.1:p.Trp405Ter nonsense NM_001407977.1:c.1215G>A NP_001394906.1:p.Trp405Ter nonsense NM_001407978.1:c.1215G>A NP_001394907.1:p.Trp405Ter nonsense NM_001407979.1:c.1212G>A NP_001394908.1:p.Trp404Ter nonsense NM_001407980.1:c.1212G>A NP_001394909.1:p.Trp404Ter nonsense NM_001407981.1:c.1212G>A NP_001394910.1:p.Trp404Ter nonsense NM_001407982.1:c.1212G>A NP_001394911.1:p.Trp404Ter nonsense NM_001407983.1:c.1212G>A NP_001394912.1:p.Trp404Ter nonsense NM_001407984.1:c.1212G>A NP_001394913.1:p.Trp404Ter nonsense NM_001407985.1:c.1212G>A NP_001394914.1:p.Trp404Ter nonsense NM_001407986.1:c.1212G>A NP_001394915.1:p.Trp404Ter nonsense NM_001407990.1:c.1212G>A NP_001394919.1:p.Trp404Ter nonsense NM_001407991.1:c.1212G>A NP_001394920.1:p.Trp404Ter nonsense NM_001407992.1:c.1212G>A NP_001394921.1:p.Trp404Ter nonsense NM_001407993.1:c.1212G>A NP_001394922.1:p.Trp404Ter nonsense NM_001408392.1:c.1209G>A NP_001395321.1:p.Trp403Ter nonsense NM_001408396.1:c.1209G>A NP_001395325.1:p.Trp403Ter nonsense NM_001408397.1:c.1209G>A NP_001395326.1:p.Trp403Ter nonsense NM_001408398.1:c.1209G>A NP_001395327.1:p.Trp403Ter nonsense NM_001408399.1:c.1209G>A NP_001395328.1:p.Trp403Ter nonsense NM_001408400.1:c.1209G>A NP_001395329.1:p.Trp403Ter nonsense NM_001408401.1:c.1209G>A NP_001395330.1:p.Trp403Ter nonsense NM_001408402.1:c.1209G>A NP_001395331.1:p.Trp403Ter nonsense NM_001408403.1:c.1209G>A NP_001395332.1:p.Trp403Ter nonsense NM_001408404.1:c.1209G>A NP_001395333.1:p.Trp403Ter nonsense NM_001408406.1:c.1206G>A NP_001395335.1:p.Trp402Ter nonsense NM_001408407.1:c.1206G>A NP_001395336.1:p.Trp402Ter nonsense NM_001408408.1:c.1206G>A NP_001395337.1:p.Trp402Ter nonsense NM_001408409.1:c.1203G>A NP_001395338.1:p.Trp401Ter nonsense NM_001408410.1:c.1140G>A NP_001395339.1:p.Trp380Ter nonsense NM_001408411.1:c.1137G>A NP_001395340.1:p.Trp379Ter nonsense NM_001408412.1:c.1134G>A NP_001395341.1:p.Trp378Ter nonsense NM_001408413.1:c.1134G>A NP_001395342.1:p.Trp378Ter nonsense NM_001408414.1:c.1134G>A NP_001395343.1:p.Trp378Ter nonsense NM_001408415.1:c.1134G>A NP_001395344.1:p.Trp378Ter nonsense NM_001408416.1:c.1134G>A NP_001395345.1:p.Trp378Ter nonsense NM_001408418.1:c.1098G>A NP_001395347.1:p.Trp366Ter nonsense NM_001408419.1:c.1098G>A NP_001395348.1:p.Trp366Ter nonsense NM_001408420.1:c.1098G>A NP_001395349.1:p.Trp366Ter nonsense NM_001408421.1:c.1095G>A NP_001395350.1:p.Trp365Ter nonsense NM_001408422.1:c.1095G>A NP_001395351.1:p.Trp365Ter nonsense NM_001408423.1:c.1095G>A NP_001395352.1:p.Trp365Ter nonsense NM_001408424.1:c.1095G>A NP_001395353.1:p.Trp365Ter nonsense NM_001408425.1:c.1092G>A NP_001395354.1:p.Trp364Ter nonsense NM_001408426.1:c.1092G>A NP_001395355.1:p.Trp364Ter nonsense NM_001408427.1:c.1092G>A NP_001395356.1:p.Trp364Ter nonsense NM_001408428.1:c.1092G>A NP_001395357.1:p.Trp364Ter nonsense NM_001408429.1:c.1092G>A NP_001395358.1:p.Trp364Ter nonsense NM_001408430.1:c.1092G>A NP_001395359.1:p.Trp364Ter nonsense NM_001408431.1:c.1092G>A NP_001395360.1:p.Trp364Ter nonsense NM_001408432.1:c.1089G>A NP_001395361.1:p.Trp363Ter nonsense NM_001408433.1:c.1089G>A NP_001395362.1:p.Trp363Ter nonsense NM_001408434.1:c.1089G>A NP_001395363.1:p.Trp363Ter nonsense NM_001408435.1:c.1089G>A NP_001395364.1:p.Trp363Ter nonsense NM_001408436.1:c.1089G>A NP_001395365.1:p.Trp363Ter nonsense NM_001408437.1:c.1089G>A NP_001395366.1:p.Trp363Ter nonsense NM_001408438.1:c.1089G>A NP_001395367.1:p.Trp363Ter nonsense NM_001408439.1:c.1089G>A NP_001395368.1:p.Trp363Ter nonsense NM_001408440.1:c.1089G>A NP_001395369.1:p.Trp363Ter nonsense NM_001408441.1:c.1089G>A NP_001395370.1:p.Trp363Ter nonsense NM_001408442.1:c.1089G>A NP_001395371.1:p.Trp363Ter nonsense NM_001408443.1:c.1089G>A NP_001395372.1:p.Trp363Ter nonsense NM_001408444.1:c.1089G>A NP_001395373.1:p.Trp363Ter nonsense NM_001408445.1:c.1086G>A NP_001395374.1:p.Trp362Ter nonsense NM_001408446.1:c.1086G>A NP_001395375.1:p.Trp362Ter nonsense NM_001408447.1:c.1086G>A NP_001395376.1:p.Trp362Ter nonsense NM_001408448.1:c.1086G>A NP_001395377.1:p.Trp362Ter nonsense NM_001408450.1:c.1086G>A NP_001395379.1:p.Trp362Ter nonsense NM_001408451.1:c.1080G>A NP_001395380.1:p.Trp360Ter nonsense NM_001408452.1:c.1074G>A NP_001395381.1:p.Trp358Ter nonsense NM_001408453.1:c.1074G>A NP_001395382.1:p.Trp358Ter nonsense NM_001408454.1:c.1074G>A NP_001395383.1:p.Trp358Ter nonsense NM_001408455.1:c.1074G>A NP_001395384.1:p.Trp358Ter nonsense NM_001408456.1:c.1074G>A NP_001395385.1:p.Trp358Ter nonsense NM_001408457.1:c.1074G>A NP_001395386.1:p.Trp358Ter nonsense NM_001408458.1:c.1071G>A NP_001395387.1:p.Trp357Ter nonsense NM_001408459.1:c.1071G>A NP_001395388.1:p.Trp357Ter nonsense NM_001408460.1:c.1071G>A NP_001395389.1:p.Trp357Ter nonsense NM_001408461.1:c.1071G>A NP_001395390.1:p.Trp357Ter nonsense NM_001408462.1:c.1071G>A NP_001395391.1:p.Trp357Ter nonsense NM_001408463.1:c.1071G>A NP_001395392.1:p.Trp357Ter nonsense NM_001408464.1:c.1071G>A NP_001395393.1:p.Trp357Ter nonsense NM_001408465.1:c.1071G>A NP_001395394.1:p.Trp357Ter nonsense NM_001408466.1:c.1071G>A NP_001395395.1:p.Trp357Ter nonsense NM_001408467.1:c.1071G>A NP_001395396.1:p.Trp357Ter nonsense NM_001408468.1:c.1068G>A NP_001395397.1:p.Trp356Ter nonsense NM_001408469.1:c.1068G>A NP_001395398.1:p.Trp356Ter nonsense NM_001408470.1:c.1068G>A NP_001395399.1:p.Trp356Ter nonsense NM_001408472.1:c.1212G>A NP_001395401.1:p.Trp404Ter nonsense NM_001408473.1:c.1209G>A NP_001395402.1:p.Trp403Ter nonsense NM_001408474.1:c.1014G>A NP_001395403.1:p.Trp338Ter nonsense NM_001408475.1:c.1011G>A NP_001395404.1:p.Trp337Ter nonsense NM_001408476.1:c.1011G>A NP_001395405.1:p.Trp337Ter nonsense NM_001408478.1:c.1005G>A NP_001395407.1:p.Trp335Ter nonsense NM_001408479.1:c.1005G>A NP_001395408.1:p.Trp335Ter nonsense NM_001408480.1:c.1005G>A NP_001395409.1:p.Trp335Ter nonsense NM_001408481.1:c.1002G>A NP_001395410.1:p.Trp334Ter nonsense NM_001408482.1:c.1002G>A NP_001395411.1:p.Trp334Ter nonsense NM_001408483.1:c.1002G>A NP_001395412.1:p.Trp334Ter nonsense NM_001408484.1:c.1002G>A NP_001395413.1:p.Trp334Ter nonsense NM_001408485.1:c.1002G>A NP_001395414.1:p.Trp334Ter nonsense NM_001408489.1:c.1002G>A NP_001395418.1:p.Trp334Ter nonsense NM_001408490.1:c.1002G>A NP_001395419.1:p.Trp334Ter nonsense NM_001408491.1:c.1002G>A NP_001395420.1:p.Trp334Ter nonsense NM_001408492.1:c.999G>A NP_001395421.1:p.Trp333Ter nonsense NM_001408493.1:c.999G>A NP_001395422.1:p.Trp333Ter nonsense NM_001408494.1:c.975G>A NP_001395423.1:p.Trp325Ter nonsense NM_001408495.1:c.969G>A NP_001395424.1:p.Trp323Ter nonsense NM_001408496.1:c.951G>A NP_001395425.1:p.Trp317Ter nonsense NM_001408497.1:c.951G>A NP_001395426.1:p.Trp317Ter nonsense NM_001408498.1:c.951G>A NP_001395427.1:p.Trp317Ter nonsense NM_001408499.1:c.951G>A NP_001395428.1:p.Trp317Ter nonsense NM_001408500.1:c.951G>A NP_001395429.1:p.Trp317Ter nonsense NM_001408501.1:c.951G>A NP_001395430.1:p.Trp317Ter nonsense NM_001408502.1:c.948G>A NP_001395431.1:p.Trp316Ter nonsense NM_001408503.1:c.948G>A NP_001395432.1:p.Trp316Ter nonsense NM_001408504.1:c.948G>A NP_001395433.1:p.Trp316Ter nonsense NM_001408505.1:c.945G>A NP_001395434.1:p.Trp315Ter nonsense NM_001408506.1:c.888G>A NP_001395435.1:p.Trp296Ter nonsense NM_001408507.1:c.885G>A NP_001395436.1:p.Trp295Ter nonsense NM_001408508.1:c.876G>A NP_001395437.1:p.Trp292Ter nonsense NM_001408509.1:c.873G>A NP_001395438.1:p.Trp291Ter nonsense NM_001408510.1:c.834G>A NP_001395439.1:p.Trp278Ter nonsense NM_001408511.1:c.831G>A NP_001395440.1:p.Trp277Ter nonsense NM_001408512.1:c.711G>A NP_001395441.1:p.Trp237Ter nonsense NM_007297.4:c.4383G>A NP_009228.2:p.Trp1461Ter nonsense NM_007298.4:c.1212G>A NP_009229.2:p.Trp404Ter nonsense NM_007299.4:c.1212G>A NP_009230.2:p.Trp404Ter nonsense NM_007300.4:c.4587G>A NP_009231.2:p.Trp1529Ter nonsense NM_007304.2:c.1212G>A NP_009235.2:p.Trp404Ter nonsense NR_027676.2:n.4701G>A non-coding transcript variant NC_000017.11:g.43074482C>T NC_000017.10:g.41226499C>T NG_005905.2:g.143502G>A LRG_292:g.143502G>A LRG_292t1:c.4524G>A LRG_292p1:p.Trp1508Ter U14680.1:n.4643G>A - Protein change
- W1508*, W1529*, W1461*, W404*, W1381*, W1460*, W1465*, W1480*, W1506*, W1507*, W1530*, W277*, W292*, W325*, W333*, W362*, W364*, W366*, W379*, W401*, W402*, W405*, W1211*, W1379*, W1397*, W1420*, W1438*, W1459*, W1464*, W1467*, W1482*, W1489*, W1503*, W295*, W315*, W357*, W358*, W365*, W427*, W639*, W1395*, W1396*, W1419*, W1437*, W1439*, W1441*, W1488*, W1505*, W1528*, W237*, W291*, W296*, W335*, W337*, W338*, W363*, W380*, W640*, W1212*, W1339*, W1380*, W1418*, W1436*, W1466*, W1481*, W1504*, W278*, W316*, W317*, W323*, W334*, W356*, W360*, W378*, W403*, W426*
- Other names
-
NP_009225.1:p.Trp1508Ter
4643G>A
- Canonical SPDI
- NC_000017.11:43074481:C: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.
- -
- 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 |
13040 | 14846 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000048586.30 | |
| Pathogenic (10) |
reviewed by expert panel
|
Sep 8, 2016 | RCV000077575.21 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV000129129.20 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jun 18, 2023 | RCV000236102.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762998.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 16, 2019 | RCV001001033.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 3, 2023 | RCV003492388.1 | |
|
Inherited breast cancer and ovarian cancer
|
Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2024 | RCV004584141.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 08, 2016)
|
reviewed by expert panel
Method: curation
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000300134.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
|
|
Pathogenic
(Oct 30, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: no
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000223755.1
First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
|
|
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Pathogenic
(Oct 31, 2018)
|
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: SCV000893443.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001158145.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu … (more)
The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. (less)
|
|
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Pathogenic
(Jul 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000494394.2
First in ClinVar: May 29, 2016 Last updated: Aug 08, 2020 |
Comment:
Variant summary: BRCA1 c.4524G>A (p.Trp1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA1 c.4524G>A (p.Trp1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Nov 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Accession: SCV002025933.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Geographic origin: South Africa
Testing laboratory: National Health Laboratory Service (NHLS)
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Pathogenic
(Aug 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489091.2
First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 18, 2023)
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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: SCV000292523.12
First in ClinVar: Jul 24, 2016 Last updated: Jun 24, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary Breast and Ovarian Cancer Syndrome
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046230.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to … (more)
This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296378.5
First in ClinVar: Jun 08, 2015 Last updated: Jan 06, 2024 |
Comment:
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast … (more)
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003809690.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004240268.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004212734.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jul 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000806952.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
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Pathogenic
(Jan 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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GeneKor MSA
Accession: SCV000693539.2
First in ClinVar: Oct 09, 2016 Last updated: Apr 24, 2020 |
Comment:
This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results … (more)
This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221). (less)
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Pathogenic
(Aug 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271319.4
First in ClinVar: May 29, 2016 Last updated: Jul 03, 2020 |
Comment:
The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC … (more)
The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325992.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Feb 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224838.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP5, PM2, PVS1
Number of individuals with the variant: 1
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Pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000912007.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000076599.13
First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp1508*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp1508*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004817662.1
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 variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000183847.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at … (more)
The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Inherited breast cancer and ovarian cancer
Affected status: yes
Allele origin:
germline
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NHS Central & South Genomic Laboratory Hub
Accession: SCV005068248.1
First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024 |
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Pathogenic
(May 29, 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: SCV000145114.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 6
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Ashkenazi
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Australian
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Observation 5:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American, Central/Eastern European
Observation 6:
Number of individuals with the variant: 11
Ethnicity/Population group: Western European
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Italian
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Native American
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Pathogenic
(Nov 02, 2010)
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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: SCV000109378.2
First in ClinVar: Dec 23, 2013 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: SCV001550566.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587406.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927922.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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Pathogenic
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004243983.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Comment:
Comment:
The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7.
Comment:
Variant summary: BRCA1 c.4524G>A (p.Trp1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441)
Comment:
This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic.
Comment:
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221).
Comment:
The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Comment:
PP5, PM2, PVS1
Comment:
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Trp1508*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
Variant allele predicted to encode a truncated non-functional protein.
Comment:
The BRCA1 c.4524G>A; p.Trp1508Ter variant (rs80356885), also known as 4643G>A, is reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Bu 2016, Couch 2015, Kang 2015, Laitman 2011, Loman 2001, Lynce 2015,) or other cancer types (Lowery 2018, Rebbeck 2018, Walsh 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 55221), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bu R et al. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. Int J Cancer. 2016 Sep 1;139(5):1091-7. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Kang E et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat. 2015 May;151(1):157-68. Laitman Y et al. Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. Breast Cancer Res Treat. 2011 Jun;127(2):489-95. Loman N et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst. 2001 Aug 15;93(16):1215-23. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. Lynce F et al. Deleterious BRCA1/2 mutations in an urban population of Black women. Breast Cancer Res Treat. 2015 Aug;153(1):201-9. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7.
Comment:
Variant summary: BRCA1 c.4524G>A (p.Trp1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251348 control chromosomes. c.4524G>A has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Loman_2001, Phelan_2002, Judkins_2005, Laitman_2011, Walsh_2011, Bayraktar_2012, Bu_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Laitman et al., 2011; Walsh et al., 2011; Bayraktar et al., 2012; Lynce et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4643G>A; This variant is associated with the following publications: (PMID: 26250392, 22009639, 11504767, 24830819, 29506128, 34290354, 34657373, 28888541, 33858029, 25525159, 20960228, 12402332, 22006311, 27082205, 29446198, 30199306, 33087929, 25863477, 29021639, 27208206, 25452441)
Comment:
This variant is also referred to as c.4524G>A (p.Trp 1508Ter) in the literature. This nonsense variant found in exon 15 of 24 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer as well as other types of cancer (PMID: PMID: 25863477, 11504767, 25452441, 27082205, 22006311). Loss-of-function variation in BRCA1 is an established mechanism of disease (PMID: 20301425). The c.4587G>A (p.Trp1529Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4587G>A (p.Trp1529Ter) variant is classified as Pathogenic.
Comment:
This nonsense variant causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant variant has been described in individuals with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 30199306 (2018), 29506128 (2018), 29446198 (2018), 29021639 (2017), 27082205 (2016), 26250392 (2015), 25863477 (2015)). Based on the available information, this variant is classified as pathogenic.
Comment:
This variant is a single amino acid change from Tryptophan to a termination codon at amino acid residue 1508 of the BRCA1 gene. It results in a truncated non-functional protein. Truncating variants in the BRCA1 gene are known to be pathogenic. This variant is also known as c.4643G>A in the literature. This particular truncation has been reported in the literature in an individual from a high risk breast and/or ovarian cancer family (PMID: 20960228) in individuals with breast cancer (PMID: 25863477, 11504767) and in an individual with peritoneal cancer (PMID: 22006311). The mutation database ClinVar contains entries for this variant (Variation ID: 55221).
Comment:
The p.Trp1508X variant in BRCA1 has been reported in >13 individuals with BRCA1-related cancers (Loman 2001, Laitman 2011, Walsh 2011, Bayraktar 2012, Lowery 2018, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1508, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA1 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 55221). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
Comment:
PP5, PM2, PVS1
Comment:
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 30199306, 32862574, 33471991, 34290354, 35464868; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Trp1508*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and/or peritoneal cancer (PMID: 11504767, 20960228, 22006311, 25452441, 25863477, 27082205). This variant is also known as 4643G>A. ClinVar contains an entry for this variant (Variation ID: 55221). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant changes 1 nucleotide in exon 14 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast, ovarian and peritoneal cancer and in a breast cancer case-control meta-analysis in 3 cases and 1 unaffected control (PMID: 11504767, 22006311, 23982851, 25452441, 26250392, 27082205, 29021639, 33471991; Leiden Open Variation Database DB-ID BRCA1_000323) and also in suspected hereditary breast and ovarian cancer families (PMID: 12402332, 20960228, 25863477). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.W1508* pathogenic mutation (also known as c.4524G>A), located in coding exon 13 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4524. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun;127:489-95; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Loman N et al. J. Natl. Cancer Inst., 2001 Aug;93:1215-23; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Bu R et al. Int. J. Cancer. 2016 Sep;139:1091-7; Briceño-Balcázar I et al. Colomb. Med. 2017 Jun;48(2):58-63; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906; Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9; Demir S et al. J BUON;25:1337-1347; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). Of note, this alteration is also designated as 4643G>A in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | DOI: 10.3389/fgene.2022.834265 |
| Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience. | Van der Merwe NC | Frontiers in genetics | 2022 | PMID: 35464868 |
| The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit. | Frugtniet B | BJOG : an international journal of obstetrics and gynaecology | 2022 | PMID: 34657373 |
| Prevalence and predictors of germline BRCA1 and BRCA2 mutations among young patients with breast cancer in Jordan. | Abdel-Razeq H | Scientific reports | 2021 | PMID: 34290354 |
| 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 |
| Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey. | Demir S | Journal of B.U.ON. : official journal of the Balkan Union of Oncology | 2020 | PMID: 32862574 |
| Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer. | Abulkhair O | Journal of global oncology | 2018 | PMID: 30199306 |
| Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. | Lowery MA | Journal of the National Cancer Institute | 2018 | PMID: 29506128 |
| Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
| Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia. | Briceño-Balcázar I | Colombia medica (Cali, Colombia) | 2017 | PMID: 29021639 |
| Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. | Lilyquist J | Gynecologic oncology | 2017 | PMID: 28888541 |
| New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. | Plaskocinska I | Journal of medical genetics | 2016 | PMID: 27208206 |
| Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis. | Bu R | International journal of cancer | 2016 | PMID: 27082205 |
| Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory. | Strom CM | PloS one | 2015 | PMID: 26295337 |
| Deleterious BRCA1/2 mutations in an urban population of Black women. | Lynce F | Breast cancer research and treatment | 2015 | PMID: 26250392 |
| The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. | Kang E | Breast cancer research and treatment | 2015 | PMID: 25863477 |
| Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
| Association of BRCA1 germline mutations in young onset triple-negative breast cancer (TNBC). | Andrés R | Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico | 2014 | PMID: 23982851 |
| Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. | Bayraktar S | Cancer | 2012 | PMID: 22009639 |
| Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
| Germline mutations in BRCA1 and BRCA2 genes in ethnically diverse high risk families in Israel. | Laitman Y | Breast cancer research and treatment | 2011 | PMID: 20960228 |
| Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. | Borg A | Human mutation | 2010 | PMID: 20104584 |
| Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. | Judkins T | Cancer research | 2005 | PMID: 16267036 |
| A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families. | Phelan CM | Human mutation | 2002 | PMID: 12402332 |
| Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. | Loman N | Journal of the National Cancer Institute | 2001 | PMID: 11504767 |
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Text-mined citations for rs80356885 ...
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Record last updated Oct 27, 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.