Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.2475del (p.Asp825fs)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Apr 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.2475del (p.Asp825fs)
Variation ID: 37472 Accession: VCV000037472.68
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43093056 (GRCh38) [ NCBI UCSC ] 17: 41245073 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 27, 2014 Nov 24, 2024 Apr 22, 2016 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.2475del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Asp825fs frameshift NM_001407571.1:c.2262del NP_001394500.1:p.Asp754fs frameshift NM_001407581.1:c.2475del NP_001394510.1:p.Asp825fs frameshift NM_001407582.1:c.2475del NP_001394511.1:p.Asp825fs frameshift NM_001407583.1:c.2475del NP_001394512.1:p.Asp825fs frameshift NM_001407585.1:c.2475del NP_001394514.1:p.Asp825fs frameshift NM_001407587.1:c.2472del NP_001394516.1:p.Asp824fs frameshift NM_001407590.1:c.2472del NP_001394519.1:p.Asp824fs frameshift NM_001407591.1:c.2472del NP_001394520.1:p.Asp824fs frameshift NM_001407593.1:c.2475del NP_001394522.1:p.Asp825fs frameshift NM_001407594.1:c.2475del NP_001394523.1:p.Asp825fs frameshift NM_001407596.1:c.2475del NP_001394525.1:p.Asp825fs frameshift NM_001407597.1:c.2475del NP_001394526.1:p.Asp825fs frameshift NM_001407598.1:c.2475del NP_001394527.1:p.Asp825fs frameshift NM_001407602.1:c.2475del NP_001394531.1:p.Asp825fs frameshift NM_001407603.1:c.2475del NP_001394532.1:p.Asp825fs frameshift NM_001407605.1:c.2475del NP_001394534.1:p.Asp825fs frameshift NM_001407610.1:c.2472del NP_001394539.1:p.Asp824fs frameshift NM_001407611.1:c.2472del NP_001394540.1:p.Asp824fs frameshift NM_001407612.1:c.2472del NP_001394541.1:p.Asp824fs frameshift NM_001407613.1:c.2472del NP_001394542.1:p.Asp824fs frameshift NM_001407614.1:c.2472del NP_001394543.1:p.Asp824fs frameshift NM_001407615.1:c.2472del NP_001394544.1:p.Asp824fs frameshift NM_001407616.1:c.2475del NP_001394545.1:p.Asp825fs frameshift NM_001407617.1:c.2475del NP_001394546.1:p.Asp825fs frameshift NM_001407618.1:c.2475del NP_001394547.1:p.Asp825fs frameshift NM_001407619.1:c.2475del NP_001394548.1:p.Asp825fs frameshift NM_001407620.1:c.2475del NP_001394549.1:p.Asp825fs frameshift NM_001407621.1:c.2475del NP_001394550.1:p.Asp825fs frameshift NM_001407622.1:c.2475del NP_001394551.1:p.Asp825fs frameshift NM_001407623.1:c.2475del NP_001394552.1:p.Asp825fs frameshift NM_001407624.1:c.2475del NP_001394553.1:p.Asp825fs frameshift NM_001407625.1:c.2475del NP_001394554.1:p.Asp825fs frameshift NM_001407626.1:c.2475del NP_001394555.1:p.Asp825fs frameshift NM_001407627.1:c.2472del NP_001394556.1:p.Asp824fs frameshift NM_001407628.1:c.2472del NP_001394557.1:p.Asp824fs frameshift NM_001407629.1:c.2472del NP_001394558.1:p.Asp824fs frameshift NM_001407630.1:c.2472del NP_001394559.1:p.Asp824fs frameshift NM_001407631.1:c.2472del NP_001394560.1:p.Asp824fs frameshift NM_001407632.1:c.2472del NP_001394561.1:p.Asp824fs frameshift NM_001407633.1:c.2472del NP_001394562.1:p.Asp824fs frameshift NM_001407634.1:c.2472del NP_001394563.1:p.Asp824fs frameshift NM_001407635.1:c.2472del NP_001394564.1:p.Asp824fs frameshift NM_001407636.1:c.2472del NP_001394565.1:p.Asp824fs frameshift NM_001407637.1:c.2472del NP_001394566.1:p.Asp824fs frameshift NM_001407638.1:c.2472del NP_001394567.1:p.Asp824fs frameshift NM_001407639.1:c.2475del NP_001394568.1:p.Asp825fs frameshift NM_001407640.1:c.2475del NP_001394569.1:p.Asp825fs frameshift NM_001407641.1:c.2475del NP_001394570.1:p.Asp825fs frameshift NM_001407642.1:c.2475del NP_001394571.1:p.Asp825fs frameshift NM_001407644.1:c.2472del NP_001394573.1:p.Asp824fs frameshift NM_001407645.1:c.2472del NP_001394574.1:p.Asp824fs frameshift NM_001407646.1:c.2466del NP_001394575.1:p.Asp822fs frameshift NM_001407647.1:c.2466del NP_001394576.1:p.Asp822fs frameshift NM_001407648.1:c.2352del NP_001394577.1:p.Asp784fs frameshift NM_001407649.1:c.2349del NP_001394578.1:p.Asp783fs frameshift NM_001407652.1:c.2475del NP_001394581.1:p.Asp825fs frameshift NM_001407653.1:c.2397del NP_001394582.1:p.Asp799fs frameshift NM_001407654.1:c.2397del NP_001394583.1:p.Asp799fs frameshift NM_001407655.1:c.2397del NP_001394584.1:p.Asp799fs frameshift NM_001407656.1:c.2397del NP_001394585.1:p.Asp799fs frameshift NM_001407657.1:c.2397del NP_001394586.1:p.Asp799fs frameshift NM_001407658.1:c.2397del NP_001394587.1:p.Asp799fs frameshift NM_001407659.1:c.2394del NP_001394588.1:p.Asp798fs frameshift NM_001407660.1:c.2394del NP_001394589.1:p.Asp798fs frameshift NM_001407661.1:c.2394del NP_001394590.1:p.Asp798fs frameshift NM_001407662.1:c.2394del NP_001394591.1:p.Asp798fs frameshift NM_001407663.1:c.2397del NP_001394592.1:p.Asp799fs frameshift NM_001407664.1:c.2352del NP_001394593.1:p.Asp784fs frameshift NM_001407665.1:c.2352del NP_001394594.1:p.Asp784fs frameshift NM_001407666.1:c.2352del NP_001394595.1:p.Asp784fs frameshift NM_001407667.1:c.2352del NP_001394596.1:p.Asp784fs frameshift NM_001407668.1:c.2352del NP_001394597.1:p.Asp784fs frameshift NM_001407669.1:c.2352del NP_001394598.1:p.Asp784fs frameshift NM_001407670.1:c.2349del NP_001394599.1:p.Asp783fs frameshift NM_001407671.1:c.2349del NP_001394600.1:p.Asp783fs frameshift NM_001407672.1:c.2349del NP_001394601.1:p.Asp783fs frameshift NM_001407673.1:c.2349del NP_001394602.1:p.Asp783fs frameshift NM_001407674.1:c.2352del NP_001394603.1:p.Asp784fs frameshift NM_001407675.1:c.2352del NP_001394604.1:p.Asp784fs frameshift NM_001407676.1:c.2352del NP_001394605.1:p.Asp784fs frameshift NM_001407677.1:c.2352del NP_001394606.1:p.Asp784fs frameshift NM_001407678.1:c.2352del NP_001394607.1:p.Asp784fs frameshift NM_001407679.1:c.2352del NP_001394608.1:p.Asp784fs frameshift NM_001407680.1:c.2352del NP_001394609.1:p.Asp784fs frameshift NM_001407681.1:c.2352del NP_001394610.1:p.Asp784fs frameshift NM_001407682.1:c.2352del NP_001394611.1:p.Asp784fs frameshift NM_001407683.1:c.2352del NP_001394612.1:p.Asp784fs frameshift NM_001407684.1:c.2475del NP_001394613.1:p.Asp825fs frameshift NM_001407685.1:c.2349del NP_001394614.1:p.Asp783fs frameshift NM_001407686.1:c.2349del NP_001394615.1:p.Asp783fs frameshift NM_001407687.1:c.2349del NP_001394616.1:p.Asp783fs frameshift NM_001407688.1:c.2349del NP_001394617.1:p.Asp783fs frameshift NM_001407689.1:c.2349del NP_001394618.1:p.Asp783fs frameshift NM_001407690.1:c.2349del NP_001394619.1:p.Asp783fs frameshift NM_001407691.1:c.2349del NP_001394620.1:p.Asp783fs frameshift NM_001407692.1:c.2334del NP_001394621.1:p.Asp778fs frameshift NM_001407694.1:c.2334del NP_001394623.1:p.Asp778fs frameshift NM_001407695.1:c.2334del NP_001394624.1:p.Asp778fs frameshift NM_001407696.1:c.2334del NP_001394625.1:p.Asp778fs frameshift NM_001407697.1:c.2334del NP_001394626.1:p.Asp778fs frameshift NM_001407698.1:c.2334del NP_001394627.1:p.Asp778fs frameshift NM_001407724.1:c.2334del NP_001394653.1:p.Asp778fs frameshift NM_001407725.1:c.2334del NP_001394654.1:p.Asp778fs frameshift NM_001407726.1:c.2334del NP_001394655.1:p.Asp778fs frameshift NM_001407727.1:c.2334del NP_001394656.1:p.Asp778fs frameshift NM_001407728.1:c.2334del NP_001394657.1:p.Asp778fs frameshift NM_001407729.1:c.2334del NP_001394658.1:p.Asp778fs frameshift NM_001407730.1:c.2334del NP_001394659.1:p.Asp778fs frameshift NM_001407731.1:c.2334del NP_001394660.1:p.Asp778fs frameshift NM_001407732.1:c.2334del NP_001394661.1:p.Asp778fs frameshift NM_001407733.1:c.2334del NP_001394662.1:p.Asp778fs frameshift NM_001407734.1:c.2334del NP_001394663.1:p.Asp778fs frameshift NM_001407735.1:c.2334del NP_001394664.1:p.Asp778fs frameshift NM_001407736.1:c.2334del NP_001394665.1:p.Asp778fs frameshift NM_001407737.1:c.2334del NP_001394666.1:p.Asp778fs frameshift NM_001407738.1:c.2334del NP_001394667.1:p.Asp778fs frameshift NM_001407739.1:c.2334del NP_001394668.1:p.Asp778fs frameshift NM_001407740.1:c.2331del NP_001394669.1:p.Asp777fs frameshift NM_001407741.1:c.2331del NP_001394670.1:p.Asp777fs frameshift NM_001407742.1:c.2331del NP_001394671.1:p.Asp777fs frameshift NM_001407743.1:c.2331del NP_001394672.1:p.Asp777fs frameshift NM_001407744.1:c.2331del NP_001394673.1:p.Asp777fs frameshift NM_001407745.1:c.2331del NP_001394674.1:p.Asp777fs frameshift NM_001407746.1:c.2331del NP_001394675.1:p.Asp777fs frameshift NM_001407747.1:c.2331del NP_001394676.1:p.Asp777fs frameshift NM_001407748.1:c.2331del NP_001394677.1:p.Asp777fs frameshift NM_001407749.1:c.2331del NP_001394678.1:p.Asp777fs frameshift NM_001407750.1:c.2334del NP_001394679.1:p.Asp778fs frameshift NM_001407751.1:c.2334del NP_001394680.1:p.Asp778fs frameshift NM_001407752.1:c.2334del NP_001394681.1:p.Asp778fs frameshift NM_001407838.1:c.2331del NP_001394767.1:p.Asp777fs frameshift NM_001407839.1:c.2331del NP_001394768.1:p.Asp777fs frameshift NM_001407841.1:c.2331del NP_001394770.1:p.Asp777fs frameshift NM_001407842.1:c.2331del NP_001394771.1:p.Asp777fs frameshift NM_001407843.1:c.2331del NP_001394772.1:p.Asp777fs frameshift NM_001407844.1:c.2331del NP_001394773.1:p.Asp777fs frameshift NM_001407845.1:c.2331del NP_001394774.1:p.Asp777fs frameshift NM_001407846.1:c.2331del NP_001394775.1:p.Asp777fs frameshift NM_001407847.1:c.2331del NP_001394776.1:p.Asp777fs frameshift NM_001407848.1:c.2331del NP_001394777.1:p.Asp777fs frameshift NM_001407849.1:c.2331del NP_001394778.1:p.Asp777fs frameshift NM_001407850.1:c.2334del NP_001394779.1:p.Asp778fs frameshift NM_001407851.1:c.2334del NP_001394780.1:p.Asp778fs frameshift NM_001407852.1:c.2334del NP_001394781.1:p.Asp778fs frameshift NM_001407853.1:c.2262del NP_001394782.1:p.Asp754fs frameshift NM_001407854.1:c.2475del NP_001394783.1:p.Asp825fs frameshift NM_001407858.1:c.2475del NP_001394787.1:p.Asp825fs frameshift NM_001407859.1:c.2475del NP_001394788.1:p.Asp825fs frameshift NM_001407860.1:c.2472del NP_001394789.1:p.Asp824fs frameshift NM_001407861.1:c.2472del NP_001394790.1:p.Asp824fs frameshift NM_001407862.1:c.2274del NP_001394791.1:p.Asp758fs frameshift NM_001407863.1:c.2352del NP_001394792.1:p.Asp784fs frameshift NM_001407874.1:c.2271del NP_001394803.1:p.Asp757fs frameshift NM_001407875.1:c.2271del NP_001394804.1:p.Asp757fs frameshift NM_001407879.1:c.2265del NP_001394808.1:p.Asp755fs frameshift NM_001407881.1:c.2265del NP_001394810.1:p.Asp755fs frameshift NM_001407882.1:c.2265del NP_001394811.1:p.Asp755fs frameshift NM_001407884.1:c.2265del NP_001394813.1:p.Asp755fs frameshift NM_001407885.1:c.2265del NP_001394814.1:p.Asp755fs frameshift NM_001407886.1:c.2265del NP_001394815.1:p.Asp755fs frameshift NM_001407887.1:c.2265del NP_001394816.1:p.Asp755fs frameshift NM_001407889.1:c.2265del NP_001394818.1:p.Asp755fs frameshift NM_001407894.1:c.2262del NP_001394823.1:p.Asp754fs frameshift NM_001407895.1:c.2262del NP_001394824.1:p.Asp754fs frameshift NM_001407896.1:c.2262del NP_001394825.1:p.Asp754fs frameshift NM_001407897.1:c.2262del NP_001394826.1:p.Asp754fs frameshift NM_001407898.1:c.2262del NP_001394827.1:p.Asp754fs frameshift NM_001407899.1:c.2262del NP_001394828.1:p.Asp754fs frameshift NM_001407900.1:c.2265del NP_001394829.1:p.Asp755fs frameshift NM_001407902.1:c.2265del NP_001394831.1:p.Asp755fs frameshift NM_001407904.1:c.2265del NP_001394833.1:p.Asp755fs frameshift NM_001407906.1:c.2265del NP_001394835.1:p.Asp755fs frameshift NM_001407907.1:c.2265del NP_001394836.1:p.Asp755fs frameshift NM_001407908.1:c.2265del NP_001394837.1:p.Asp755fs frameshift NM_001407909.1:c.2265del NP_001394838.1:p.Asp755fs frameshift NM_001407910.1:c.2265del NP_001394839.1:p.Asp755fs frameshift NM_001407915.1:c.2262del NP_001394844.1:p.Asp754fs frameshift NM_001407916.1:c.2262del NP_001394845.1:p.Asp754fs frameshift NM_001407917.1:c.2262del NP_001394846.1:p.Asp754fs frameshift NM_001407918.1:c.2262del NP_001394847.1:p.Asp754fs frameshift NM_001407919.1:c.2352del NP_001394848.1:p.Asp784fs frameshift NM_001407920.1:c.2211del NP_001394849.1:p.Asp737fs frameshift NM_001407921.1:c.2211del NP_001394850.1:p.Asp737fs frameshift NM_001407922.1:c.2211del NP_001394851.1:p.Asp737fs frameshift NM_001407923.1:c.2211del NP_001394852.1:p.Asp737fs frameshift NM_001407924.1:c.2211del NP_001394853.1:p.Asp737fs frameshift NM_001407925.1:c.2211del NP_001394854.1:p.Asp737fs frameshift NM_001407926.1:c.2211del NP_001394855.1:p.Asp737fs frameshift NM_001407927.1:c.2211del NP_001394856.1:p.Asp737fs frameshift NM_001407928.1:c.2211del NP_001394857.1:p.Asp737fs frameshift NM_001407929.1:c.2211del NP_001394858.1:p.Asp737fs frameshift NM_001407930.1:c.2208del NP_001394859.1:p.Asp736fs frameshift NM_001407931.1:c.2208del NP_001394860.1:p.Asp736fs frameshift NM_001407932.1:c.2208del NP_001394861.1:p.Asp736fs frameshift NM_001407933.1:c.2211del NP_001394862.1:p.Asp737fs frameshift NM_001407934.1:c.2208del NP_001394863.1:p.Asp736fs frameshift NM_001407935.1:c.2211del NP_001394864.1:p.Asp737fs frameshift NM_001407936.1:c.2208del NP_001394865.1:p.Asp736fs frameshift NM_001407937.1:c.2352del NP_001394866.1:p.Asp784fs frameshift NM_001407938.1:c.2352del NP_001394867.1:p.Asp784fs frameshift NM_001407939.1:c.2352del NP_001394868.1:p.Asp784fs frameshift NM_001407940.1:c.2349del NP_001394869.1:p.Asp783fs frameshift NM_001407941.1:c.2349del NP_001394870.1:p.Asp783fs frameshift NM_001407942.1:c.2334del NP_001394871.1:p.Asp778fs frameshift NM_001407943.1:c.2331del NP_001394872.1:p.Asp777fs frameshift NM_001407944.1:c.2334del NP_001394873.1:p.Asp778fs frameshift NM_001407945.1:c.2334del NP_001394874.1:p.Asp778fs frameshift NM_001407946.1:c.2142del NP_001394875.1:p.Asp714fs frameshift NM_001407947.1:c.2142del NP_001394876.1:p.Asp714fs frameshift NM_001407948.1:c.2142del NP_001394877.1:p.Asp714fs frameshift NM_001407949.1:c.2142del NP_001394878.1:p.Asp714fs frameshift NM_001407950.1:c.2142del NP_001394879.1:p.Asp714fs frameshift NM_001407951.1:c.2142del NP_001394880.1:p.Asp714fs frameshift NM_001407952.1:c.2142del NP_001394881.1:p.Asp714fs frameshift NM_001407953.1:c.2142del NP_001394882.1:p.Asp714fs frameshift NM_001407954.1:c.2139del NP_001394883.1:p.Asp713fs frameshift NM_001407955.1:c.2139del NP_001394884.1:p.Asp713fs frameshift NM_001407956.1:c.2139del NP_001394885.1:p.Asp713fs frameshift NM_001407957.1:c.2142del NP_001394886.1:p.Asp714fs frameshift NM_001407958.1:c.2139del NP_001394887.1:p.Asp713fs frameshift NM_001407959.1:c.2094del NP_001394888.1:p.Asp698fs frameshift NM_001407960.1:c.2094del NP_001394889.1:p.Asp698fs frameshift NM_001407962.1:c.2091del NP_001394891.1:p.Asp697fs frameshift NM_001407963.1:c.2094del NP_001394892.1:p.Asp698fs frameshift NM_001407964.1:c.2331del NP_001394893.1:p.Asp777fs frameshift NM_001407965.1:c.1971del NP_001394894.1:p.Asp657fs frameshift NM_001407966.1:c.1587del NP_001394895.1:p.Asp529fs frameshift NM_001407967.1:c.1587del NP_001394896.1:p.Asp529fs frameshift NM_001407968.1:c.788-917del intron variant NM_001407969.1:c.788-917del intron variant NM_001407970.1:c.787+1688del intron variant NM_001407971.1:c.787+1688del intron variant NM_001407972.1:c.784+1688del intron variant NM_001407973.1:c.787+1688del intron variant NM_001407974.1:c.787+1688del intron variant NM_001407975.1:c.787+1688del intron variant NM_001407976.1:c.787+1688del intron variant NM_001407977.1:c.787+1688del intron variant NM_001407978.1:c.787+1688del intron variant NM_001407979.1:c.787+1688del intron variant NM_001407980.1:c.787+1688del intron variant NM_001407981.1:c.787+1688del intron variant NM_001407982.1:c.787+1688del intron variant NM_001407983.1:c.787+1688del intron variant NM_001407984.1:c.784+1688del intron variant NM_001407985.1:c.784+1688del intron variant NM_001407986.1:c.784+1688del intron variant NM_001407990.1:c.787+1688del intron variant NM_001407991.1:c.784+1688del intron variant NM_001407992.1:c.784+1688del intron variant NM_001407993.1:c.787+1688del intron variant NM_001408392.1:c.784+1688del intron variant NM_001408396.1:c.784+1688del intron variant NM_001408397.1:c.784+1688del intron variant NM_001408398.1:c.784+1688del intron variant NM_001408399.1:c.784+1688del intron variant NM_001408400.1:c.784+1688del intron variant NM_001408401.1:c.784+1688del intron variant NM_001408402.1:c.784+1688del intron variant NM_001408403.1:c.787+1688del intron variant NM_001408404.1:c.787+1688del intron variant NM_001408406.1:c.790+1685del intron variant NM_001408407.1:c.784+1688del intron variant NM_001408408.1:c.778+1688del intron variant NM_001408409.1:c.709+1688del intron variant NM_001408410.1:c.646+1688del intron variant NM_001408411.1:c.709+1688del intron variant NM_001408412.1:c.709+1688del intron variant NM_001408413.1:c.706+1688del intron variant NM_001408414.1:c.709+1688del intron variant NM_001408415.1:c.709+1688del intron variant NM_001408416.1:c.706+1688del intron variant NM_001408418.1:c.671-2024del intron variant NM_001408419.1:c.671-2024del intron variant NM_001408420.1:c.671-2024del intron variant NM_001408421.1:c.668-2024del intron variant NM_001408422.1:c.671-2024del intron variant NM_001408423.1:c.671-2024del intron variant NM_001408424.1:c.668-2024del intron variant NM_001408425.1:c.664+1688del intron variant NM_001408426.1:c.664+1688del intron variant NM_001408427.1:c.664+1688del intron variant NM_001408428.1:c.664+1688del intron variant NM_001408429.1:c.664+1688del intron variant NM_001408430.1:c.664+1688del intron variant NM_001408431.1:c.668-2024del intron variant NM_001408432.1:c.661+1688del intron variant NM_001408433.1:c.661+1688del intron variant NM_001408434.1:c.661+1688del intron variant NM_001408435.1:c.661+1688del intron variant NM_001408436.1:c.664+1688del intron variant NM_001408437.1:c.664+1688del intron variant NM_001408438.1:c.664+1688del intron variant NM_001408439.1:c.664+1688del intron variant NM_001408440.1:c.664+1688del intron variant NM_001408441.1:c.664+1688del intron variant NM_001408442.1:c.664+1688del intron variant NM_001408443.1:c.664+1688del intron variant NM_001408444.1:c.664+1688del intron variant NM_001408445.1:c.661+1688del intron variant NM_001408446.1:c.661+1688del intron variant NM_001408447.1:c.661+1688del intron variant NM_001408448.1:c.661+1688del intron variant NM_001408450.1:c.661+1688del intron variant NM_001408451.1:c.652+1688del intron variant NM_001408452.1:c.646+1688del intron variant NM_001408453.1:c.646+1688del intron variant NM_001408454.1:c.646+1688del intron variant NM_001408455.1:c.646+1688del intron variant NM_001408456.1:c.646+1688del intron variant NM_001408457.1:c.646+1688del intron variant NM_001408458.1:c.646+1688del intron variant NM_001408459.1:c.646+1688del intron variant NM_001408460.1:c.646+1688del intron variant NM_001408461.1:c.646+1688del intron variant NM_001408462.1:c.643+1688del intron variant NM_001408463.1:c.643+1688del intron variant NM_001408464.1:c.643+1688del intron variant NM_001408465.1:c.643+1688del intron variant NM_001408466.1:c.646+1688del intron variant NM_001408467.1:c.646+1688del intron variant NM_001408468.1:c.643+1688del intron variant NM_001408469.1:c.646+1688del intron variant NM_001408470.1:c.643+1688del intron variant NM_001408472.1:c.787+1688del intron variant NM_001408473.1:c.784+1688del intron variant NM_001408474.1:c.586+1688del intron variant NM_001408475.1:c.583+1688del intron variant NM_001408476.1:c.586+1688del intron variant NM_001408478.1:c.577+1688del intron variant NM_001408479.1:c.577+1688del intron variant NM_001408480.1:c.577+1688del intron variant NM_001408481.1:c.577+1688del intron variant NM_001408482.1:c.577+1688del intron variant NM_001408483.1:c.577+1688del intron variant NM_001408484.1:c.577+1688del intron variant NM_001408485.1:c.577+1688del intron variant NM_001408489.1:c.577+1688del intron variant NM_001408490.1:c.574+1688del intron variant NM_001408491.1:c.574+1688del intron variant NM_001408492.1:c.577+1688del intron variant NM_001408493.1:c.574+1688del intron variant NM_001408494.1:c.548-2024del intron variant NM_001408495.1:c.545-2024del intron variant NM_001408496.1:c.523+1688del intron variant NM_001408497.1:c.523+1688del intron variant NM_001408498.1:c.523+1688del intron variant NM_001408499.1:c.523+1688del intron variant NM_001408500.1:c.523+1688del intron variant NM_001408501.1:c.523+1688del intron variant NM_001408502.1:c.454+1688del intron variant NM_001408503.1:c.520+1688del intron variant NM_001408504.1:c.520+1688del intron variant NM_001408505.1:c.520+1688del intron variant NM_001408506.1:c.461-2024del intron variant NM_001408507.1:c.461-2024del intron variant NM_001408508.1:c.451+1688del intron variant NM_001408509.1:c.451+1688del intron variant NM_001408510.1:c.406+1688del intron variant NM_001408511.1:c.404-2024del intron variant NM_001408512.1:c.283+1688del intron variant NM_001408513.1:c.577+1688del intron variant NM_001408514.1:c.577+1688del intron variant NM_007297.4:c.2334del NP_009228.2:p.Asp778fs frameshift NM_007298.4:c.787+1688del intron variant NM_007299.4:c.787+1688del intron variant NM_007300.4:c.2475del NP_009231.2:p.Asp825fs frameshift NR_027676.1:n.2611delC NC_000017.11:g.43093056del NC_000017.10:g.41245073del NG_005905.2:g.124928del LRG_292:g.124928del LRG_292t1:c.2475del LRG_292p1:p.Asp825Glufs U14680.1:n.2594delC - Protein change
- D778fs, D825fs, D529fs, D657fs, D698fs, D755fs, D697fs, D713fs, D714fs, D757fs, D758fs, D822fs, D736fs, D737fs, D783fs, D784fs, D798fs, D824fs, D754fs, D777fs, D799fs
- Other names
-
2594delC
- Canonical SPDI
- NC_000017.11:43093055:G:
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
13050 | 14856 | |
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 (14) |
reviewed by expert panel
|
Apr 22, 2016 | RCV000031053.31 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000047850.28 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 31, 2022 | RCV000131352.20 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000236906.34 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785403.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 25, 2019 | RCV001000474.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2022 | RCV002482928.8 | |
|
BRCA1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 2024 | RCV004554621.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 22, 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: SCV000282281.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
|
|
Pathogenic
(Mar 25, 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: SCV001157346.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The BRCA1 c.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome … (more)
The BRCA1 c.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome (Cunningham 2014, Pennington 2013, Schneegans 2012). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 37472). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it 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 Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Pennington K et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013; 119(2):332-8. Schneegans S et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012; 11(2):181-8. (less)
|
|
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Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000296289.7
First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024 |
Comment:
This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this … (more)
This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 31263571 (2019), 24504028 (2014), 22811390 (2013), 20104584 (2010), 18465347 (2008), 8595428 (1995)), pancreatic cancer (PMID: 29433453 (2018)), renal cancer (PMID: 32782288 (2020)), and prostate cancer (PMID: 22516946 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428903.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447426.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Sex: female
|
|
|
Pathogenic
(Jun 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292513.14
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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 … (more)
Frameshift 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, and considered a common founder variant in the Scandinavian population (Plummer 1995, Janaviius 2010, Leongamornlert 2012, Schneegans 2012, Pennington 2013, Cunningham 2014, Maxwell 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2594delC; This variant is associated with the following publications: (PMID: 22811390, 22516946, 17694537, 8595428, 23747895, 26833046, 28476184, 29625052, 26689913, 24504028, 22160602, 23199084, 24728189, 23704984, 17688236, 25452441, 18465347, 20104584, 28049106, 28087643, 27798111, 27375368, 28776284, 28831036, 29339979, 29433453, 30720243, 30322717, 32050665, 31263571, 31883735, 11391658, 34399810, 32719484, 33087929) (less)
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Pathogenic
(Mar 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215067.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551018.7
First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024 |
|
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Pathogenic
(Nov 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000195906.1
First in ClinVar: May 06, 2016 Last updated: May 06, 2016 |
Tissue: Blood
|
|
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Pathogenic
(Jul 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Medical Genetics, Oslo University Hospital
Accession: SCV000564368.1
First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
Number of individuals with the variant: 15
|
|
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Pathogenic
(Apr 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000586884.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
|
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Pathogenic
(Jun 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698959.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense … (more)
Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.2515delC, c.2679_2682delGAAA, c.2681_2682delAA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121366 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature, and has been described as a common mutation in individuals of Scandinavian ancestry. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: no
Allele origin:
germline
|
Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434305.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result … (more)
This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result in an unstable transcript that is degraded by nonsense-mediated decay, a well-established mechanism of disease for the BRCA1 gene (Borg 2010). In the literature, this variant has been observed in individuals with breast cancer, ovarian cancer, and prostate cancer and has been noted to occur more commonly in individuals of Scandinavian descent (Cunningham (2014), Janavicius (2010), Larsen (2013), Leongamornlert (2012), Schneegans (2012), Thomassen (2008)). Based on this information, we consider this variant to be pathogenic. PS4; PVS1 (less)
Indication for testing: Family history of breast cancer
|
|
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Pathogenic
(Apr 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial breast-ovarian cancer 1
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434971.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted … (more)
This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 8595428, 18465347). Therefore, the c.2475delC (p.Asp825Glufs*21) variant in the BRCA1 gene is classified as pathogenic. (less)
|
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Pathogenic
(Sep 25, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449778.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 18
|
|
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Pathogenic
(Oct 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325365.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
|
|
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Pathogenic
(Apr 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677643.2
First in ClinVar: Jan 06, 2018 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Feb 12, 2022)
|
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: SCV002790692.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Apr 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003811755.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000075863.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp825Glufs*21) 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.Asp825Glufs*21) 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 present in population databases (rs80357970, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 8595428, 18465347, 20104584, 22160602, 22516946, 23199084, 23704984, 24307375, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as 2594delC. ClinVar contains an entry for this variant (Variation ID: 37472). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 31, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000683038.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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
(Aug 15, 2023)
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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: SCV004818176.1
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 deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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
(Oct 14, 2019)
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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
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848278.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Asp825GlufsX21 variant in BRCA1 has been reported in >25 individuals with BRCA1-related cancers and has been reported as a founder variant in Scandinavian populations … (more)
The p.Asp825GlufsX21 variant in BRCA1 has been reported in >25 individuals with BRCA1-related cancers and has been reported as a founder variant in Scandinavian populations (Pennington 2013, Cunningham 2014, Maxwell 2017, Hakansson 1997, BIC database). It has also been identified in 1/113380 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 825 and leads to a premature termination codon 21 amino acids downstream. This alteration is then 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. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37472). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. (less)
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Pathogenic
(Dec 08, 2021)
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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: SCV000186327.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing … (more)
The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing a translational frameshift with a predicted alternate stop codon (p.D825Efs*21). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date and has been described as a Scandinavian/Northern European founder mutation (Plummer SJ et al. Hum. Mol. Genet. 1995 Oct;4:1989-91; Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Lancaster JM et al. Br. J. Cancer. 1998 Dec;78:1417-20; Johannsson O et al. Eur. J. Cancer. 1999 Aug;35:1248-57; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Thomassen M et al. Acta Oncol. 2008;47:772-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Janaviius R. EPMA J. 2010 Sep;1:397-412; Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Schneegans SM et al. Fam. Cancer, 2012 Jun;11:181-8; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Maxwell KN et al. Nat Commun, 2017 08;8:319; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in familial prostate cancer cohorts (Leongamornlert D et al. Br. J. Cancer. 2012 May;106:1697-701; Li D et al. Front Biosci (Landmark Ed). 2013 Jun;18:1445-59), as well as a uterine serous carcinoma cohort (Pennington KP et al. Cancer, 2013 Jan;119:332-8). It was also seen in a male patient with pancreatic cancer (Ibrahim M et al. BMC Cancer. 2018 02;18(1):179). Of note, this alteration is also designated as 2594delC and rs80357970 in published literature. 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
(May 27, 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: yes
Allele origin:
germline
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005045946.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
PVS1; PM5_PTC_Strong
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Pathogenic
(Mar 04, 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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199736.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Jul 23, 2024)
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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: SCV005413233.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PM5_strong, PVS1
Number of individuals with the variant: 2
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Pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Ovarian neoplasm
Affected status: yes
Allele origin:
germline
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923975.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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Pathogenic
(Feb 01, 2024)
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no assertion criteria provided
Method: clinical testing
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BRCA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004782881.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian … (more)
The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian cancer (Maxwell et al. 2017. PubMed ID: 28831036; Cunningham et al. 2014. PubMed ID: 24504028), pancreatic cancer (Ibrahim et al. 2018. PubMed ID: 29433453), and prostate cancer (Leongamornlert et al. 2012. PubMed ID: 22516946). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37472/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 04, 2013)
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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: SCV000053647.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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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,
unknown
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144450.2
First in ClinVar: Apr 01, 2014 Last updated: Sep 27, 2014 |
Observation 1:
Number of individuals with the variant: 26
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Denmark
Observation 3:
Number of individuals with the variant: 3
Geographic origin: Sweden
Observation 4:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 5:
Number of individuals with the variant: 4
Ethnicity/Population group: Caucasian
Geographic origin: Denmark
Observation 6:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: English
Observation 7:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Norway
Observation 8:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
Observation 9:
Number of individuals with the variant: 1
Ethnicity/Population group: Latin American, Caribbean, Mexican
Observation 10:
Number of individuals with the variant: 1
Ethnicity/Population group: Native American
Observation 11:
Number of individuals with the variant: 19
Ethnicity/Population group: Western European
Observation 12:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, Central/Eastern European
Observation 13:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, German
Observation 14:
Number of individuals with the variant: 2
Geographic origin: American
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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
|
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587221.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
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Pathogenic
(Aug 26, 2022)
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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: SCV002589097.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary breast ovarian cancer syndrome
Affected status: yes, unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749976.2
First in ClinVar: Jul 18, 2021 Last updated: Jan 26, 2024 |
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently … (more)
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 12/24/2018 by Invitae and 11/29/2016 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Observation 1:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Diagnostic, Family Testing
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-11-29
Testing laboratory interpretation: Pathogenic
Observation 2:
Clinical Features:
Family history of cancer (present)
Indication for testing: Presymptomatic, Family Testing
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-12-24
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
The BRCA1 c.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome (Cunningham 2014, Pennington 2013, Schneegans 2012). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 37472). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it 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 Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Pennington K et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013; 119(2):332-8. Schneegans S et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012; 11(2):181-8.
Comment:
This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 31263571 (2019), 24504028 (2014), 22811390 (2013), 20104584 (2010), 18465347 (2008), 8595428 (1995)), pancreatic cancer (PMID: 29433453 (2018)), renal cancer (PMID: 32782288 (2020)), and prostate cancer (PMID: 22516946 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Comment:
Frameshift 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, and considered a common founder variant in the Scandinavian population (Plummer 1995, Janaviius 2010, Leongamornlert 2012, Schneegans 2012, Pennington 2013, Cunningham 2014, Maxwell 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2594delC; This variant is associated with the following publications: (PMID: 22811390, 22516946, 17694537, 8595428, 23747895, 26833046, 28476184, 29625052, 26689913, 24504028, 22160602, 23199084, 24728189, 23704984, 17688236, 25452441, 18465347, 20104584, 28049106, 28087643, 27798111, 27375368, 28776284, 28831036, 29339979, 29433453, 30720243, 30322717, 32050665, 31263571, 31883735, 11391658, 34399810, 32719484, 33087929)
Comment:
Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.2515delC, c.2679_2682delGAAA, c.2681_2682delAA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121366 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature, and has been described as a common mutation in individuals of Scandinavian ancestry. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result in an unstable transcript that is degraded by nonsense-mediated decay, a well-established mechanism of disease for the BRCA1 gene (Borg 2010). In the literature, this variant has been observed in individuals with breast cancer, ovarian cancer, and prostate cancer and has been noted to occur more commonly in individuals of Scandinavian descent (Cunningham (2014), Janavicius (2010), Larsen (2013), Leongamornlert (2012), Schneegans (2012), Thomassen (2008)). Based on this information, we consider this variant to be pathogenic. PS4; PVS1
Comment:
This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 8595428, 18465347). Therefore, the c.2475delC (p.Asp825Glufs*21) variant in the BRCA1 gene is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asp825Glufs*21) 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 present in population databases (rs80357970, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 8595428, 18465347, 20104584, 22160602, 22516946, 23199084, 23704984, 24307375, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as 2594delC. ClinVar contains an entry for this variant (Variation ID: 37472). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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 variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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.Asp825GlufsX21 variant in BRCA1 has been reported in >25 individuals with BRCA1-related cancers and has been reported as a founder variant in Scandinavian populations (Pennington 2013, Cunningham 2014, Maxwell 2017, Hakansson 1997, BIC database). It has also been identified in 1/113380 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 825 and leads to a premature termination codon 21 amino acids downstream. This alteration is then 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. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37472). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Comment:
The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing a translational frameshift with a predicted alternate stop codon (p.D825Efs*21). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date and has been described as a Scandinavian/Northern European founder mutation (Plummer SJ et al. Hum. Mol. Genet. 1995 Oct;4:1989-91; Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Lancaster JM et al. Br. J. Cancer. 1998 Dec;78:1417-20; Johannsson O et al. Eur. J. Cancer. 1999 Aug;35:1248-57; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Thomassen M et al. Acta Oncol. 2008;47:772-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Janaviius R. EPMA J. 2010 Sep;1:397-412; Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Schneegans SM et al. Fam. Cancer, 2012 Jun;11:181-8; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Maxwell KN et al. Nat Commun, 2017 08;8:319; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in familial prostate cancer cohorts (Leongamornlert D et al. Br. J. Cancer. 2012 May;106:1697-701; Li D et al. Front Biosci (Landmark Ed). 2013 Jun;18:1445-59), as well as a uterine serous carcinoma cohort (Pennington KP et al. Cancer, 2013 Jan;119:332-8). It was also seen in a male patient with pancreatic cancer (Ibrahim M et al. BMC Cancer. 2018 02;18(1):179). Of note, this alteration is also designated as 2594delC and rs80357970 in published literature. 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.
Comment:
PVS1; PM5_PTC_Strong
Comment:
PM5_strong, PVS1
Comment:
The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian cancer (Maxwell et al. 2017. PubMed ID: 28831036; Cunningham et al. 2014. PubMed ID: 24504028), pancreatic cancer (Ibrahim et al. 2018. PubMed ID: 29433453), and prostate cancer (Leongamornlert et al. 2012. PubMed ID: 22516946). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37472/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 12/24/2018 by Invitae and 11/29/2016 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
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.2475delC; p.Asp825fs variant (rs80357970), also known as 2594delC, has been reported in multiple unrelated individuals diagnosed with hereditary breast and ovarian cancer syndrome (Cunningham 2014, Pennington 2013, Schneegans 2012). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 37472). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it 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 Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Pennington K et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013; 119(2):332-8. Schneegans S et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012; 11(2):181-8.
Comment:
This variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 31263571 (2019), 24504028 (2014), 22811390 (2013), 20104584 (2010), 18465347 (2008), 8595428 (1995)), pancreatic cancer (PMID: 29433453 (2018)), renal cancer (PMID: 32782288 (2020)), and prostate cancer (PMID: 22516946 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Comment:
Frameshift 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, and considered a common founder variant in the Scandinavian population (Plummer 1995, Janaviius 2010, Leongamornlert 2012, Schneegans 2012, Pennington 2013, Cunningham 2014, Maxwell 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2594delC; This variant is associated with the following publications: (PMID: 22811390, 22516946, 17694537, 8595428, 23747895, 26833046, 28476184, 29625052, 26689913, 24504028, 22160602, 23199084, 24728189, 23704984, 17688236, 25452441, 18465347, 20104584, 28049106, 28087643, 27798111, 27375368, 28776284, 28831036, 29339979, 29433453, 30720243, 30322717, 32050665, 31263571, 31883735, 11391658, 34399810, 32719484, 33087929)
Comment:
Variant summary: The BRCA1 c.2475delC (p.Asp825Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. c.2515delC, c.2679_2682delGAAA, c.2681_2682delAA). One in silico tool predicts a damaging outcome for this variant and the variant is absent in 121366 control chromosomes. The variant has been reported in numerous affected families and individuals in the literature, and has been described as a common mutation in individuals of Scandinavian ancestry. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This variant deletes a single nucleotide causing a frameshift at position 825 which leads to a premature stop codon. This variant is predicted to result in an unstable transcript that is degraded by nonsense-mediated decay, a well-established mechanism of disease for the BRCA1 gene (Borg 2010). In the literature, this variant has been observed in individuals with breast cancer, ovarian cancer, and prostate cancer and has been noted to occur more commonly in individuals of Scandinavian descent (Cunningham (2014), Janavicius (2010), Larsen (2013), Leongamornlert (2012), Schneegans (2012), Thomassen (2008)). Based on this information, we consider this variant to be pathogenic. PS4; PVS1
Comment:
This c.2475delC (p.Asp825Glufs*21) variant in exon 10 of the BRCA1 gene results in a frameshift that leads to an early stop codon that is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 8595428, 18465347). Therefore, the c.2475delC (p.Asp825Glufs*21) variant in the BRCA1 gene is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asp825Glufs*21) 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 present in population databases (rs80357970, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 8595428, 18465347, 20104584, 22160602, 22516946, 23199084, 23704984, 24307375, 24504028). It has also been observed to segregate with disease in related individuals. This variant is also known as 2594delC. ClinVar contains an entry for this variant (Variation ID: 37472). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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 variant deletes 1 nucleotide in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in a breast cancer case-control meta-analysis in 9/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001013). This variant has been reported in over a dozen individuals affected with breast, cervical, ovarian and uterine cancer (PMID: 8595428, 11389159, 11391658, 11504767, 20104584, 20807450, 21371001, 22160602, 22811390, 23704984, 24504028, 24728189) including six affected members of one family (PMID: 11391658) and has been described as a recurrent mutation in Denmark, Sweden and other northern European countries (PMID: 9150154, 9836472, 10615237, 18465347, 23199084). This variant also has been reported in individuals affected with pancreatic or prostate cancer (PMID: 22516946, 29339979). This variant has been identified in 1/250912 chromosomes 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.Asp825GlufsX21 variant in BRCA1 has been reported in >25 individuals with BRCA1-related cancers and has been reported as a founder variant in Scandinavian populations (Pennington 2013, Cunningham 2014, Maxwell 2017, Hakansson 1997, BIC database). It has also been identified in 1/113380 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 825 and leads to a premature termination codon 21 amino acids downstream. This alteration is then 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. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37472). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.
Comment:
The c.2475delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2475, causing a translational frameshift with a predicted alternate stop codon (p.D825Efs*21). This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date and has been described as a Scandinavian/Northern European founder mutation (Plummer SJ et al. Hum. Mol. Genet. 1995 Oct;4:1989-91; Johannsson O et al. Am. J. Hum. Genet. 1996 Mar;58:441-50; Håkansson S et al. Am J Hum Genet, 1997 May;60:1068-78; Lancaster JM et al. Br. J. Cancer. 1998 Dec;78:1417-20; Johannsson O et al. Eur. J. Cancer. 1999 Aug;35:1248-57; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Thomassen M et al. Acta Oncol. 2008;47:772-7; Swisher EM et al. Cancer Res, 2008 Apr;68:2581-6; Janaviius R. EPMA J. 2010 Sep;1:397-412; Norquist B et al. J Clin Oncol, 2011 Aug;29:3008-15; Schneegans SM et al. Fam. Cancer, 2012 Jun;11:181-8; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Maxwell KN et al. Nat Commun, 2017 08;8:319; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in familial prostate cancer cohorts (Leongamornlert D et al. Br. J. Cancer. 2012 May;106:1697-701; Li D et al. Front Biosci (Landmark Ed). 2013 Jun;18:1445-59), as well as a uterine serous carcinoma cohort (Pennington KP et al. Cancer, 2013 Jan;119:332-8). It was also seen in a male patient with pancreatic cancer (Ibrahim M et al. BMC Cancer. 2018 02;18(1):179). Of note, this alteration is also designated as 2594delC and rs80357970 in published literature. 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.
Comment:
PVS1; PM5_PTC_Strong
Comment:
PM5_strong, PVS1
Comment:
The BRCA1 c.2475delC variant is predicted to result in a frameshift and premature protein termination (p.Asp825Glufs*21). This variant has been reported in individuals with ovarian cancer (Maxwell et al. 2017. PubMed ID: 28831036; Cunningham et al. 2014. PubMed ID: 24504028), pancreatic cancer (Ibrahim et al. 2018. PubMed ID: 29433453), and prostate cancer (Leongamornlert et al. 2012. PubMed ID: 22516946). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/37472/). Frameshift variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Variant reported in multiple GenomeConnect-Invitae Patient Insights Network participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 12/24/2018 by Invitae and 11/29/2016 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| BRCA1 Norway: comparison of classification for BRCA1 germline variants detected in families with suspected hereditary breast and ovarian cancer between different laboratories. | Hovland HN | Familial cancer | 2022 | PMID: 34981296 |
| 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 |
| High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. | Evans DG | Journal of medical genetics | 2022 | PMID: 33758026 |
| 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 |
| Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer. | Hartman TR | Scientific reports | 2020 | PMID: 32782288 |
| High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer. | Bertelsen B | NPJ genomic medicine | 2019 | PMID: 31263571 |
| Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
| Male BRCA mutation carriers: clinical characteristics and cancer spectrum. | Ibrahim M | BMC cancer | 2018 | PMID: 29433453 |
| BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. | Heramb C | Hereditary cancer in clinical practice | 2018 | PMID: 29339979 |
| Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). | Harter P | PloS one | 2017 | PMID: 29053726 |
| BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. | Maxwell KN | Nature communications | 2017 | PMID: 28831036 |
| The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. | Song H | Human molecular genetics | 2014 | PMID: 24728189 |
| Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. | Cunningham JM | Scientific reports | 2014 | PMID: 24504028 |
| Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. | Watson CM | Human mutation | 2014 | PMID: 24307375 |
| The role of BRCA1 and BRCA2 in prostate cancer. | Li D | Frontiers in bioscience (Landmark edition) | 2013 | PMID: 23747895 |
| Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling. | Larsen MJ | PloS one | 2013 | PMID: 23704984 |
| BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. | Pennington KP | Cancer | 2013 | PMID: 22811390 |
| Germline BRCA1 mutations increase prostate cancer risk. | Leongamornlert D | British journal of cancer | 2012 | PMID: 22516946 |
| Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. | Schneegans SM | Familial cancer | 2012 | PMID: 22160602 |
| Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. | Norquist B | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21709188 |
| A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes. | Hondow HL | BMC cancer | 2011 | PMID: 21702907 |
| Identification of BRCA1-deficient ovarian cancers. | Skytte AB | Acta obstetricia et gynecologica Scandinavica | 2011 | PMID: 21371001 |
| Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. | Janavičius R | The EPMA journal | 2010 | PMID: 23199084 |
| Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age. | Turkovic L | BMC cancer | 2010 | PMID: 20807450 |
| 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 |
| BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. | Thomassen M | Acta oncologica (Stockholm, Sweden) | 2008 | PMID: 18465347 |
| Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. | Swisher EM | Cancer research | 2008 | PMID: 18413725 |
| 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 |
| Caucasian family with two independent mutations: 2594delC in BRCA1 and 5392delAG in BRCA2 gene. | Ganguly A | American journal of medical genetics | 2001 | PMID: 11391658 |
| BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age. | Bergthorsson JT | Journal of medical genetics | 2001 | PMID: 11389159 |
| Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers. | Johannsson O | European journal of cancer (Oxford, England : 1990) | 1999 | PMID: 10615237 |
| BRCA1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA1. | Lancaster JM | British journal of cancer | 1998 | PMID: 9836472 |
| Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. | Håkansson S | American journal of human genetics | 1997 | PMID: 9150154 |
| Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. | Johannsson O | American journal of human genetics | 1996 | PMID: 8644702 |
| Detection of BRCA1 mutations by the protein truncation test. | Plummer SJ | Human molecular genetics | 1995 | PMID: 8595428 |
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Text-mined citations for rs80357970 ...
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Record last updated Nov 25, 2024
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