Variant allele predicted to encode a truncated non-functional protein.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.2269del (p.Val757fs)
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
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NM_007294.4(BRCA1):c.2269del (p.Val757fs)
Variation ID: 37459 Accession: VCV000037459.33
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43093262 (GRCh38) [ NCBI UCSC ] 17: 41245279 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 1, 2014 Jun 17, 2024 Apr 22, 2016 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.2269del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Val757fs frameshift NM_001407571.1:c.2056del NP_001394500.1:p.Val686fs frameshift NM_001407581.1:c.2269del NP_001394510.1:p.Val757fs frameshift NM_001407582.1:c.2269del NP_001394511.1:p.Val757fs frameshift NM_001407583.1:c.2269del NP_001394512.1:p.Val757fs frameshift NM_001407585.1:c.2269del NP_001394514.1:p.Val757fs frameshift NM_001407587.1:c.2266del NP_001394516.1:p.Val756fs frameshift NM_001407590.1:c.2266del NP_001394519.1:p.Val756fs frameshift NM_001407591.1:c.2266del NP_001394520.1:p.Val756fs frameshift NM_001407593.1:c.2269del NP_001394522.1:p.Val757fs frameshift NM_001407594.1:c.2269del NP_001394523.1:p.Val757fs frameshift NM_001407596.1:c.2269del NP_001394525.1:p.Val757fs frameshift NM_001407597.1:c.2269del NP_001394526.1:p.Val757fs frameshift NM_001407598.1:c.2269del NP_001394527.1:p.Val757fs frameshift NM_001407602.1:c.2269del NP_001394531.1:p.Val757fs frameshift NM_001407603.1:c.2269del NP_001394532.1:p.Val757fs frameshift NM_001407605.1:c.2269del NP_001394534.1:p.Val757fs frameshift NM_001407610.1:c.2266del NP_001394539.1:p.Val756fs frameshift NM_001407611.1:c.2266del NP_001394540.1:p.Val756fs frameshift NM_001407612.1:c.2266del NP_001394541.1:p.Val756fs frameshift NM_001407613.1:c.2266del NP_001394542.1:p.Val756fs frameshift NM_001407614.1:c.2266del NP_001394543.1:p.Val756fs frameshift NM_001407615.1:c.2266del NP_001394544.1:p.Val756fs frameshift NM_001407616.1:c.2269del NP_001394545.1:p.Val757fs frameshift NM_001407617.1:c.2269del NP_001394546.1:p.Val757fs frameshift NM_001407618.1:c.2269del NP_001394547.1:p.Val757fs frameshift NM_001407619.1:c.2269del NP_001394548.1:p.Val757fs frameshift NM_001407620.1:c.2269del NP_001394549.1:p.Val757fs frameshift NM_001407621.1:c.2269del NP_001394550.1:p.Val757fs frameshift NM_001407622.1:c.2269del NP_001394551.1:p.Val757fs frameshift NM_001407623.1:c.2269del NP_001394552.1:p.Val757fs frameshift NM_001407624.1:c.2269del NP_001394553.1:p.Val757fs frameshift NM_001407625.1:c.2269del NP_001394554.1:p.Val757fs frameshift NM_001407626.1:c.2269del NP_001394555.1:p.Val757fs frameshift NM_001407627.1:c.2266del NP_001394556.1:p.Val756fs frameshift NM_001407628.1:c.2266del NP_001394557.1:p.Val756fs frameshift NM_001407629.1:c.2266del NP_001394558.1:p.Val756fs frameshift NM_001407630.1:c.2266del NP_001394559.1:p.Val756fs frameshift NM_001407631.1:c.2266del NP_001394560.1:p.Val756fs frameshift NM_001407632.1:c.2266del NP_001394561.1:p.Val756fs frameshift NM_001407633.1:c.2266del NP_001394562.1:p.Val756fs frameshift NM_001407634.1:c.2266del NP_001394563.1:p.Val756fs frameshift NM_001407635.1:c.2266del NP_001394564.1:p.Val756fs frameshift NM_001407636.1:c.2266del NP_001394565.1:p.Val756fs frameshift NM_001407637.1:c.2266del NP_001394566.1:p.Val756fs frameshift NM_001407638.1:c.2266del NP_001394567.1:p.Val756fs frameshift NM_001407639.1:c.2269del NP_001394568.1:p.Val757fs frameshift NM_001407640.1:c.2269del NP_001394569.1:p.Val757fs frameshift NM_001407641.1:c.2269del NP_001394570.1:p.Val757fs frameshift NM_001407642.1:c.2269del NP_001394571.1:p.Val757fs frameshift NM_001407644.1:c.2266del NP_001394573.1:p.Val756fs frameshift NM_001407645.1:c.2266del NP_001394574.1:p.Val756fs frameshift NM_001407646.1:c.2260del NP_001394575.1:p.Val754fs frameshift NM_001407647.1:c.2260del NP_001394576.1:p.Val754fs frameshift NM_001407648.1:c.2146del NP_001394577.1:p.Val716fs frameshift NM_001407649.1:c.2143del NP_001394578.1:p.Val715fs frameshift NM_001407652.1:c.2269del NP_001394581.1:p.Val757fs frameshift NM_001407653.1:c.2191del NP_001394582.1:p.Val731fs frameshift NM_001407654.1:c.2191del NP_001394583.1:p.Val731fs frameshift NM_001407655.1:c.2191del NP_001394584.1:p.Val731fs frameshift NM_001407656.1:c.2191del NP_001394585.1:p.Val731fs frameshift NM_001407657.1:c.2191del NP_001394586.1:p.Val731fs frameshift NM_001407658.1:c.2191del NP_001394587.1:p.Val731fs frameshift NM_001407659.1:c.2188del NP_001394588.1:p.Val730fs frameshift NM_001407660.1:c.2188del NP_001394589.1:p.Val730fs frameshift NM_001407661.1:c.2188del NP_001394590.1:p.Val730fs frameshift NM_001407662.1:c.2188del NP_001394591.1:p.Val730fs frameshift NM_001407663.1:c.2191del NP_001394592.1:p.Val731fs frameshift NM_001407664.1:c.2146del NP_001394593.1:p.Val716fs frameshift NM_001407665.1:c.2146del NP_001394594.1:p.Val716fs frameshift NM_001407666.1:c.2146del NP_001394595.1:p.Val716fs frameshift NM_001407667.1:c.2146del NP_001394596.1:p.Val716fs frameshift NM_001407668.1:c.2146del NP_001394597.1:p.Val716fs frameshift NM_001407669.1:c.2146del NP_001394598.1:p.Val716fs frameshift NM_001407670.1:c.2143del NP_001394599.1:p.Val715fs frameshift NM_001407671.1:c.2143del NP_001394600.1:p.Val715fs frameshift NM_001407672.1:c.2143del NP_001394601.1:p.Val715fs frameshift NM_001407673.1:c.2143del NP_001394602.1:p.Val715fs frameshift NM_001407674.1:c.2146del NP_001394603.1:p.Val716fs frameshift NM_001407675.1:c.2146del NP_001394604.1:p.Val716fs frameshift NM_001407676.1:c.2146del NP_001394605.1:p.Val716fs frameshift NM_001407677.1:c.2146del NP_001394606.1:p.Val716fs frameshift NM_001407678.1:c.2146del NP_001394607.1:p.Val716fs frameshift NM_001407679.1:c.2146del NP_001394608.1:p.Val716fs frameshift NM_001407680.1:c.2146del NP_001394609.1:p.Val716fs frameshift NM_001407681.1:c.2146del NP_001394610.1:p.Val716fs frameshift NM_001407682.1:c.2146del NP_001394611.1:p.Val716fs frameshift NM_001407683.1:c.2146del NP_001394612.1:p.Val716fs frameshift NM_001407684.1:c.2269del NP_001394613.1:p.Val757fs frameshift NM_001407685.1:c.2143del NP_001394614.1:p.Val715fs frameshift NM_001407686.1:c.2143del NP_001394615.1:p.Val715fs frameshift NM_001407687.1:c.2143del NP_001394616.1:p.Val715fs frameshift NM_001407688.1:c.2143del NP_001394617.1:p.Val715fs frameshift NM_001407689.1:c.2143del NP_001394618.1:p.Val715fs frameshift NM_001407690.1:c.2143del NP_001394619.1:p.Val715fs frameshift NM_001407691.1:c.2143del NP_001394620.1:p.Val715fs frameshift NM_001407692.1:c.2128del NP_001394621.1:p.Val710fs frameshift NM_001407694.1:c.2128del NP_001394623.1:p.Val710fs frameshift NM_001407695.1:c.2128del NP_001394624.1:p.Val710fs frameshift NM_001407696.1:c.2128del NP_001394625.1:p.Val710fs frameshift NM_001407697.1:c.2128del NP_001394626.1:p.Val710fs frameshift NM_001407698.1:c.2128del NP_001394627.1:p.Val710fs frameshift NM_001407724.1:c.2128del NP_001394653.1:p.Val710fs frameshift NM_001407725.1:c.2128del NP_001394654.1:p.Val710fs frameshift NM_001407726.1:c.2128del NP_001394655.1:p.Val710fs frameshift NM_001407727.1:c.2128del NP_001394656.1:p.Val710fs frameshift NM_001407728.1:c.2128del NP_001394657.1:p.Val710fs frameshift NM_001407729.1:c.2128del NP_001394658.1:p.Val710fs frameshift NM_001407730.1:c.2128del NP_001394659.1:p.Val710fs frameshift NM_001407731.1:c.2128del NP_001394660.1:p.Val710fs frameshift NM_001407732.1:c.2128del NP_001394661.1:p.Val710fs frameshift NM_001407733.1:c.2128del NP_001394662.1:p.Val710fs frameshift NM_001407734.1:c.2128del NP_001394663.1:p.Val710fs frameshift NM_001407735.1:c.2128del NP_001394664.1:p.Val710fs frameshift NM_001407736.1:c.2128del NP_001394665.1:p.Val710fs frameshift NM_001407737.1:c.2128del NP_001394666.1:p.Val710fs frameshift NM_001407738.1:c.2128del NP_001394667.1:p.Val710fs frameshift NM_001407739.1:c.2128del NP_001394668.1:p.Val710fs frameshift NM_001407740.1:c.2125del NP_001394669.1:p.Val709fs frameshift NM_001407741.1:c.2125del NP_001394670.1:p.Val709fs frameshift NM_001407742.1:c.2125del NP_001394671.1:p.Val709fs frameshift NM_001407743.1:c.2125del NP_001394672.1:p.Val709fs frameshift NM_001407744.1:c.2125del NP_001394673.1:p.Val709fs frameshift NM_001407745.1:c.2125del NP_001394674.1:p.Val709fs frameshift NM_001407746.1:c.2125del NP_001394675.1:p.Val709fs frameshift NM_001407747.1:c.2125del NP_001394676.1:p.Val709fs frameshift NM_001407748.1:c.2125del NP_001394677.1:p.Val709fs frameshift NM_001407749.1:c.2125del NP_001394678.1:p.Val709fs frameshift NM_001407750.1:c.2128del NP_001394679.1:p.Val710fs frameshift NM_001407751.1:c.2128del NP_001394680.1:p.Val710fs frameshift NM_001407752.1:c.2128del NP_001394681.1:p.Val710fs frameshift NM_001407838.1:c.2125del NP_001394767.1:p.Val709fs frameshift NM_001407839.1:c.2125del NP_001394768.1:p.Val709fs frameshift NM_001407841.1:c.2125del NP_001394770.1:p.Val709fs frameshift NM_001407842.1:c.2125del NP_001394771.1:p.Val709fs frameshift NM_001407843.1:c.2125del NP_001394772.1:p.Val709fs frameshift NM_001407844.1:c.2125del NP_001394773.1:p.Val709fs frameshift NM_001407845.1:c.2125del NP_001394774.1:p.Val709fs frameshift NM_001407846.1:c.2125del NP_001394775.1:p.Val709fs frameshift NM_001407847.1:c.2125del NP_001394776.1:p.Val709fs frameshift NM_001407848.1:c.2125del NP_001394777.1:p.Val709fs frameshift NM_001407849.1:c.2125del NP_001394778.1:p.Val709fs frameshift NM_001407850.1:c.2128del NP_001394779.1:p.Val710fs frameshift NM_001407851.1:c.2128del NP_001394780.1:p.Val710fs frameshift NM_001407852.1:c.2128del NP_001394781.1:p.Val710fs frameshift NM_001407853.1:c.2056del NP_001394782.1:p.Val686fs frameshift NM_001407854.1:c.2269del NP_001394783.1:p.Val757fs frameshift NM_001407858.1:c.2269del NP_001394787.1:p.Val757fs frameshift NM_001407859.1:c.2269del NP_001394788.1:p.Val757fs frameshift NM_001407860.1:c.2266del NP_001394789.1:p.Val756fs frameshift NM_001407861.1:c.2266del NP_001394790.1:p.Val756fs frameshift NM_001407862.1:c.2068del NP_001394791.1:p.Val690fs frameshift NM_001407863.1:c.2146del NP_001394792.1:p.Val716fs frameshift NM_001407874.1:c.2065del NP_001394803.1:p.Val689fs frameshift NM_001407875.1:c.2065del NP_001394804.1:p.Val689fs frameshift NM_001407879.1:c.2059del NP_001394808.1:p.Val687fs frameshift NM_001407881.1:c.2059del NP_001394810.1:p.Val687fs frameshift NM_001407882.1:c.2059del NP_001394811.1:p.Val687fs frameshift NM_001407884.1:c.2059del NP_001394813.1:p.Val687fs frameshift NM_001407885.1:c.2059del NP_001394814.1:p.Val687fs frameshift NM_001407886.1:c.2059del NP_001394815.1:p.Val687fs frameshift NM_001407887.1:c.2059del NP_001394816.1:p.Val687fs frameshift NM_001407889.1:c.2059del NP_001394818.1:p.Val687fs frameshift NM_001407894.1:c.2056del NP_001394823.1:p.Val686fs frameshift NM_001407895.1:c.2056del NP_001394824.1:p.Val686fs frameshift NM_001407896.1:c.2056del NP_001394825.1:p.Val686fs frameshift NM_001407897.1:c.2056del NP_001394826.1:p.Val686fs frameshift NM_001407898.1:c.2056del NP_001394827.1:p.Val686fs frameshift NM_001407899.1:c.2056del NP_001394828.1:p.Val686fs frameshift NM_001407900.1:c.2059del NP_001394829.1:p.Val687fs frameshift NM_001407902.1:c.2059del NP_001394831.1:p.Val687fs frameshift NM_001407904.1:c.2059del NP_001394833.1:p.Val687fs frameshift NM_001407906.1:c.2059del NP_001394835.1:p.Val687fs frameshift NM_001407907.1:c.2059del NP_001394836.1:p.Val687fs frameshift NM_001407908.1:c.2059del NP_001394837.1:p.Val687fs frameshift NM_001407909.1:c.2059del NP_001394838.1:p.Val687fs frameshift NM_001407910.1:c.2059del NP_001394839.1:p.Val687fs frameshift NM_001407915.1:c.2056del NP_001394844.1:p.Val686fs frameshift NM_001407916.1:c.2056del NP_001394845.1:p.Val686fs frameshift NM_001407917.1:c.2056del NP_001394846.1:p.Val686fs frameshift NM_001407918.1:c.2056del NP_001394847.1:p.Val686fs frameshift NM_001407919.1:c.2146del NP_001394848.1:p.Val716fs frameshift NM_001407920.1:c.2005del NP_001394849.1:p.Val669fs frameshift NM_001407921.1:c.2005del NP_001394850.1:p.Val669fs frameshift NM_001407922.1:c.2005del NP_001394851.1:p.Val669fs frameshift NM_001407923.1:c.2005del NP_001394852.1:p.Val669fs frameshift NM_001407924.1:c.2005del NP_001394853.1:p.Val669fs frameshift NM_001407925.1:c.2005del NP_001394854.1:p.Val669fs frameshift NM_001407926.1:c.2005del NP_001394855.1:p.Val669fs frameshift NM_001407927.1:c.2005del NP_001394856.1:p.Val669fs frameshift NM_001407928.1:c.2005del NP_001394857.1:p.Val669fs frameshift NM_001407929.1:c.2005del NP_001394858.1:p.Val669fs frameshift NM_001407930.1:c.2002del NP_001394859.1:p.Val668fs frameshift NM_001407931.1:c.2002del NP_001394860.1:p.Val668fs frameshift NM_001407932.1:c.2002del NP_001394861.1:p.Val668fs frameshift NM_001407933.1:c.2005del NP_001394862.1:p.Val669fs frameshift NM_001407934.1:c.2002del NP_001394863.1:p.Val668fs frameshift NM_001407935.1:c.2005del NP_001394864.1:p.Val669fs frameshift NM_001407936.1:c.2002del NP_001394865.1:p.Val668fs frameshift NM_001407937.1:c.2146del NP_001394866.1:p.Val716fs frameshift NM_001407938.1:c.2146del NP_001394867.1:p.Val716fs frameshift NM_001407939.1:c.2146del NP_001394868.1:p.Val716fs frameshift NM_001407940.1:c.2143del NP_001394869.1:p.Val715fs frameshift NM_001407941.1:c.2143del NP_001394870.1:p.Val715fs frameshift NM_001407942.1:c.2128del NP_001394871.1:p.Val710fs frameshift NM_001407943.1:c.2125del NP_001394872.1:p.Val709fs frameshift NM_001407944.1:c.2128del NP_001394873.1:p.Val710fs frameshift NM_001407945.1:c.2128del NP_001394874.1:p.Val710fs frameshift NM_001407946.1:c.1936del NP_001394875.1:p.Val646fs frameshift NM_001407947.1:c.1936del NP_001394876.1:p.Val646fs frameshift NM_001407948.1:c.1936del NP_001394877.1:p.Val646fs frameshift NM_001407949.1:c.1936del NP_001394878.1:p.Val646fs frameshift NM_001407950.1:c.1936del NP_001394879.1:p.Val646fs frameshift NM_001407951.1:c.1936del NP_001394880.1:p.Val646fs frameshift NM_001407952.1:c.1936del NP_001394881.1:p.Val646fs frameshift NM_001407953.1:c.1936del NP_001394882.1:p.Val646fs frameshift NM_001407954.1:c.1933del NP_001394883.1:p.Val645fs frameshift NM_001407955.1:c.1933del NP_001394884.1:p.Val645fs frameshift NM_001407956.1:c.1933del NP_001394885.1:p.Val645fs frameshift NM_001407957.1:c.1936del NP_001394886.1:p.Val646fs frameshift NM_001407958.1:c.1933del NP_001394887.1:p.Val645fs frameshift NM_001407959.1:c.1888del NP_001394888.1:p.Val630fs frameshift NM_001407960.1:c.1888del NP_001394889.1:p.Val630fs frameshift NM_001407962.1:c.1885del NP_001394891.1:p.Val629fs frameshift NM_001407963.1:c.1888del NP_001394892.1:p.Val630fs frameshift NM_001407964.1:c.2125del NP_001394893.1:p.Val709fs frameshift NM_001407965.1:c.1765del NP_001394894.1:p.Val589fs frameshift NM_001407966.1:c.1381del NP_001394895.1:p.Val461fs frameshift NM_001407967.1:c.1381del NP_001394896.1:p.Val461fs frameshift NM_001407968.1:c.788-1123del intron variant NM_001407969.1:c.788-1123del intron variant NM_001407970.1:c.787+1482del intron variant NM_001407971.1:c.787+1482del intron variant NM_001407972.1:c.784+1482del intron variant NM_001407973.1:c.787+1482del intron variant NM_001407974.1:c.787+1482del intron variant NM_001407975.1:c.787+1482del intron variant NM_001407976.1:c.787+1482del intron variant NM_001407977.1:c.787+1482del intron variant NM_001407978.1:c.787+1482del intron variant NM_001407979.1:c.787+1482del intron variant NM_001407980.1:c.787+1482del intron variant NM_001407981.1:c.787+1482del intron variant NM_001407982.1:c.787+1482del intron variant NM_001407983.1:c.787+1482del intron variant NM_001407984.1:c.784+1482del intron variant NM_001407985.1:c.784+1482del intron variant NM_001407986.1:c.784+1482del intron variant NM_001407990.1:c.787+1482del intron variant NM_001407991.1:c.784+1482del intron variant NM_001407992.1:c.784+1482del intron variant NM_001407993.1:c.787+1482del intron variant NM_001408392.1:c.784+1482del intron variant NM_001408396.1:c.784+1482del intron variant NM_001408397.1:c.784+1482del intron variant NM_001408398.1:c.784+1482del intron variant NM_001408399.1:c.784+1482del intron variant NM_001408400.1:c.784+1482del intron variant NM_001408401.1:c.784+1482del intron variant NM_001408402.1:c.784+1482del intron variant NM_001408403.1:c.787+1482del intron variant NM_001408404.1:c.787+1482del intron variant NM_001408406.1:c.790+1479del intron variant NM_001408407.1:c.784+1482del intron variant NM_001408408.1:c.778+1482del intron variant NM_001408409.1:c.709+1482del intron variant NM_001408410.1:c.646+1482del intron variant NM_001408411.1:c.709+1482del intron variant NM_001408412.1:c.709+1482del intron variant NM_001408413.1:c.706+1482del intron variant NM_001408414.1:c.709+1482del intron variant NM_001408415.1:c.709+1482del intron variant NM_001408416.1:c.706+1482del intron variant NM_001408418.1:c.671-2230del intron variant NM_001408419.1:c.671-2230del intron variant NM_001408420.1:c.671-2230del intron variant NM_001408421.1:c.668-2230del intron variant NM_001408422.1:c.671-2230del intron variant NM_001408423.1:c.671-2230del intron variant NM_001408424.1:c.668-2230del intron variant NM_001408425.1:c.664+1482del intron variant NM_001408426.1:c.664+1482del intron variant NM_001408427.1:c.664+1482del intron variant NM_001408428.1:c.664+1482del intron variant NM_001408429.1:c.664+1482del intron variant NM_001408430.1:c.664+1482del intron variant NM_001408431.1:c.668-2230del intron variant NM_001408432.1:c.661+1482del intron variant NM_001408433.1:c.661+1482del intron variant NM_001408434.1:c.661+1482del intron variant NM_001408435.1:c.661+1482del intron variant NM_001408436.1:c.664+1482del intron variant NM_001408437.1:c.664+1482del intron variant NM_001408438.1:c.664+1482del intron variant NM_001408439.1:c.664+1482del intron variant NM_001408440.1:c.664+1482del intron variant NM_001408441.1:c.664+1482del intron variant NM_001408442.1:c.664+1482del intron variant NM_001408443.1:c.664+1482del intron variant NM_001408444.1:c.664+1482del intron variant NM_001408445.1:c.661+1482del intron variant NM_001408446.1:c.661+1482del intron variant NM_001408447.1:c.661+1482del intron variant NM_001408448.1:c.661+1482del intron variant NM_001408450.1:c.661+1482del intron variant NM_001408451.1:c.652+1482del intron variant NM_001408452.1:c.646+1482del intron variant NM_001408453.1:c.646+1482del intron variant NM_001408454.1:c.646+1482del intron variant NM_001408455.1:c.646+1482del intron variant NM_001408456.1:c.646+1482del intron variant NM_001408457.1:c.646+1482del intron variant NM_001408458.1:c.646+1482del intron variant NM_001408459.1:c.646+1482del intron variant NM_001408460.1:c.646+1482del intron variant NM_001408461.1:c.646+1482del intron variant NM_001408462.1:c.643+1482del intron variant NM_001408463.1:c.643+1482del intron variant NM_001408464.1:c.643+1482del intron variant NM_001408465.1:c.643+1482del intron variant NM_001408466.1:c.646+1482del intron variant NM_001408467.1:c.646+1482del intron variant NM_001408468.1:c.643+1482del intron variant NM_001408469.1:c.646+1482del intron variant NM_001408470.1:c.643+1482del intron variant NM_001408472.1:c.787+1482del intron variant NM_001408473.1:c.784+1482del intron variant NM_001408474.1:c.586+1482del intron variant NM_001408475.1:c.583+1482del intron variant NM_001408476.1:c.586+1482del intron variant NM_001408478.1:c.577+1482del intron variant NM_001408479.1:c.577+1482del intron variant NM_001408480.1:c.577+1482del intron variant NM_001408481.1:c.577+1482del intron variant NM_001408482.1:c.577+1482del intron variant NM_001408483.1:c.577+1482del intron variant NM_001408484.1:c.577+1482del intron variant NM_001408485.1:c.577+1482del intron variant NM_001408489.1:c.577+1482del intron variant NM_001408490.1:c.574+1482del intron variant NM_001408491.1:c.574+1482del intron variant NM_001408492.1:c.577+1482del intron variant NM_001408493.1:c.574+1482del intron variant NM_001408494.1:c.548-2230del intron variant NM_001408495.1:c.545-2230del intron variant NM_001408496.1:c.523+1482del intron variant NM_001408497.1:c.523+1482del intron variant NM_001408498.1:c.523+1482del intron variant NM_001408499.1:c.523+1482del intron variant NM_001408500.1:c.523+1482del intron variant NM_001408501.1:c.523+1482del intron variant NM_001408502.1:c.454+1482del intron variant NM_001408503.1:c.520+1482del intron variant NM_001408504.1:c.520+1482del intron variant NM_001408505.1:c.520+1482del intron variant NM_001408506.1:c.461-2230del intron variant NM_001408507.1:c.461-2230del intron variant NM_001408508.1:c.451+1482del intron variant NM_001408509.1:c.451+1482del intron variant NM_001408510.1:c.406+1482del intron variant NM_001408511.1:c.404-2230del intron variant NM_001408512.1:c.283+1482del intron variant NM_001408513.1:c.577+1482del intron variant NM_001408514.1:c.577+1482del intron variant NM_007294.3:c.2269delG frameshift NM_007297.4:c.2128del NP_009228.2:p.Val710fs frameshift NM_007298.4:c.787+1482del intron variant NM_007299.4:c.787+1482del intron variant NM_007300.3:c.2269delG NM_007300.4:c.2269del NP_009231.2:p.Val757fs frameshift NR_027676.1:n.2403delG NC_000017.11:g.43093264del NC_000017.10:g.41245281del NG_005905.2:g.124722del LRG_292:g.124722del LRG_292t1:c.2267del LRG_292p1:p.Val757Phefs U14680.1:n.2388delG - Protein change
- V757fs, V710fs, V686fs, V690fs, V754fs, V461fs, V630fs, V669fs, V689fs, V730fs, V646fs, V668fs, V687fs, V715fs, V716fs, V756fs, V589fs, V629fs, V645fs, V709fs, V731fs
- Other names
-
2388delG
- Canonical SPDI
- NC_000017.11:43093261:CCC:CC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRCA1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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 (9) |
reviewed by expert panel
|
Apr 22, 2016 | RCV000031040.23 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 4, 2022 | RCV000215693.16 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Nov 14, 2018 | RCV000486157.16 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 14, 2023 | RCV000496582.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 24, 2017 | RCV000769719.10 |
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. |
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|---|---|---|---|---|---|
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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: SCV000282276.1
First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
|
|
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Pathogenic
(Nov 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001584605.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568420.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 17, 2019 |
Comment:
This deletion of one nucleotide in BRCA1 is denoted c.2269delG at the cDNA level and p.Val757PhefsX8 (V757FfsX8) at the protein level. The normal sequence, with … (more)
This deletion of one nucleotide in BRCA1 is denoted c.2269delG at the cDNA level and p.Val757PhefsX8 (V757FfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAGG[delG]TTTTG. The deletion causes a frameshift which changes a Valine to a Phenylalanine at codon 757, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2269delG, also published as 2388delG using alternate nomenclature, has been reported in patients with personal and/or family histories of breast and ovarian cancer (Stoppa-Lyonnet 1997, Rashid 2006, Ramus 2007, Stegel 2011, Kang 2015, Minucci 2015, Kwong 2016). We consider this variant to be pathogenic. (less)
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Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV003927258.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
A known pathogenic variant was detected in the BRCA1 gene (p.Val757fs). This sequence change creates a premature translational stop signal (p.Val757Phefs*8) in the BRCA1 gene. … (more)
A known pathogenic variant was detected in the BRCA1 gene (p.Val757fs). This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic. (less)
Age: 50-59 years
Sex: female
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Pathogenic
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004211736.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Oct 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901139.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Pathogenic
(May 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360676.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: BRCA1 c.2269delG (p.Val757PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA1 c.2269delG (p.Val757PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. c.2269delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kowalick_2018, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 02, 2020)
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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 Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499618.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Apr 13, 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
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000911348.4
First in ClinVar: May 19, 2019 Last updated: Jan 08, 2022 |
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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least seven individuals and families affected with breast and ovarian cancer (PMID: 8764110, 9150149, 12181777, 16998791, 21232165, 25863477, 30040829). This variant has been identified in 1/251198 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
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000325310.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: research
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Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: no
Allele origin:
germline
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV002762796.2
First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023 |
Comment:
PVS1, PS4_STR PM2_SUP
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Pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000275788.5
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.2269delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2269, causing … (more)
The c.2269delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2269, causing a translational frameshift with a predicted alternate stop codon (p.V757Ffs*8). This mutation has been identified in multiple families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Sobol H et al. Cancer Res. 1996 Jul;56:3216-9; Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Liede A et al. Am. J. Hum. Genet. 2002 Sep;71:595-606; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Rashid MU et al. BMC Cancer 2016 08;16(1):673). Of note, this alteration is also designated as 2388delG 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
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550583.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Val757PhefsX8 variant was identified in 5 of 830 proband chromosomes (frequency: 0.006) from individuals or families with ovarian and breast cancers of French … (more)
The BRCA1 p.Val757PhefsX8 variant was identified in 5 of 830 proband chromosomes (frequency: 0.006) from individuals or families with ovarian and breast cancers of French ethnicity (Berchuck_1998, Sobol_1996, Stoppa-Lyonnet_1997). The variant was also identified in dbSNP (ID: rs80357583) as “With Pathogenic allele”; in Clinvar as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Study description, by the Consortium of Investigators of Modifiers of BRCA1/2 University of Cambridge, by Ambry Genetics, by Breast Cancer Information Core; and Sharing Clinical Reports Project. The variant was also identified in Cosmic, UMD 46x with a casual classification, in BIC 10X as class 5 casual, and in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was further identified in the Exome Aggregation Consortium database (August 8, 2016) in 2 of 121384 chromosomes (frequency: 0.00002) in the following populations: South Asian in 1 of 16508 chromosomes (frequency: 0.00006), European (Non-Finnish) in 1 of 66726 chromosomes (frequency: 0.00002) but was not seen in African, East Asian, European (Finnish) and Latino populations. The variant was not identified in LOVD-IARC, GeneInsight COGR, Fanconi Anemia Mutation Databases, the 1000 Genomes Project and the NHLBI GO Exome Sequencing Project. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.2269delG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 757 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(Mar 02, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV004244097.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
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Pathogenic
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000144362.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 7
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Pakistani
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
|
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Pathogenic
(Dec 14, 2009)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: not provided
Allele origin:
germline
|
Sharing Clinical Reports Project (SCRP)
Accession: SCV000053634.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
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Pathogenic
(Jan 31, 2014)
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no assertion criteria provided
Method: research
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000587204.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
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Pathogenic
(Mar 29, 2017)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000778760.1
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
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Pathogenic
(Mar 31, 2023)
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no assertion criteria provided
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Lab, PINUM Cancer Hospital
Accession: SCV004011755.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Age: 20-29 years
Sex: female
Ethnicity/Population group: Pakistani
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Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic.
Comment:
This deletion of one nucleotide in BRCA1 is denoted c.2269delG at the cDNA level and p.Val757PhefsX8 (V757FfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAGG[delG]TTTTG. The deletion causes a frameshift which changes a Valine to a Phenylalanine at codon 757, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2269delG, also published as 2388delG using alternate nomenclature, has been reported in patients with personal and/or family histories of breast and ovarian cancer (Stoppa-Lyonnet 1997, Rashid 2006, Ramus 2007, Stegel 2011, Kang 2015, Minucci 2015, Kwong 2016). We consider this variant to be pathogenic.
Comment:
A known pathogenic variant was detected in the BRCA1 gene (p.Val757fs). This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: BRCA1 c.2269delG (p.Val757PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. c.2269delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kowalick_2018, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least seven individuals and families affected with breast and ovarian cancer (PMID: 8764110, 9150149, 12181777, 16998791, 21232165, 25863477, 30040829). This variant has been identified in 1/251198 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:
PVS1, PS4_STR PM2_SUP
Comment:
The c.2269delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2269, causing a translational frameshift with a predicted alternate stop codon (p.V757Ffs*8). This mutation has been identified in multiple families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Sobol H et al. Cancer Res. 1996 Jul;56:3216-9; Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Liede A et al. Am. J. Hum. Genet. 2002 Sep;71:595-606; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Rashid MU et al. BMC Cancer 2016 08;16(1):673). Of note, this alteration is also designated as 2388delG 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:
The BRCA1 p.Val757PhefsX8 variant was identified in 5 of 830 proband chromosomes (frequency: 0.006) from individuals or families with ovarian and breast cancers of French ethnicity (Berchuck_1998, Sobol_1996, Stoppa-Lyonnet_1997). The variant was also identified in dbSNP (ID: rs80357583) as “With Pathogenic allele”; in Clinvar as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Study description, by the Consortium of Investigators of Modifiers of BRCA1/2 University of Cambridge, by Ambry Genetics, by Breast Cancer Information Core; and Sharing Clinical Reports Project. The variant was also identified in Cosmic, UMD 46x with a casual classification, in BIC 10X as class 5 casual, and in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was further identified in the Exome Aggregation Consortium database (August 8, 2016) in 2 of 121384 chromosomes (frequency: 0.00002) in the following populations: South Asian in 1 of 16508 chromosomes (frequency: 0.00006), European (Non-Finnish) in 1 of 66726 chromosomes (frequency: 0.00002) but was not seen in African, East Asian, European (Finnish) and Latino populations. The variant was not identified in LOVD-IARC, GeneInsight COGR, Fanconi Anemia Mutation Databases, the 1000 Genomes Project and the NHLBI GO Exome Sequencing Project. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.2269delG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 757 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
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:
This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic.
Comment:
This deletion of one nucleotide in BRCA1 is denoted c.2269delG at the cDNA level and p.Val757PhefsX8 (V757FfsX8) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAGG[delG]TTTTG. The deletion causes a frameshift which changes a Valine to a Phenylalanine at codon 757, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.2269delG, also published as 2388delG using alternate nomenclature, has been reported in patients with personal and/or family histories of breast and ovarian cancer (Stoppa-Lyonnet 1997, Rashid 2006, Ramus 2007, Stegel 2011, Kang 2015, Minucci 2015, Kwong 2016). We consider this variant to be pathogenic.
Comment:
A known pathogenic variant was detected in the BRCA1 gene (p.Val757fs). This sequence change creates a premature translational stop signal (p.Val757Phefs*8) 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 (rs80357583, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150149, 25863477, 26306726, 27553291). This variant is also known as 2388delG. ClinVar contains an entry for this variant (Variation ID: 37459). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: BRCA1 c.2269delG (p.Val757PhefsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. c.2269delG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Kowalick_2018, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in at least seven individuals and families affected with breast and ovarian cancer (PMID: 8764110, 9150149, 12181777, 16998791, 21232165, 25863477, 30040829). This variant has been identified in 1/251198 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:
PVS1, PS4_STR PM2_SUP
Comment:
The c.2269delG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2269, causing a translational frameshift with a predicted alternate stop codon (p.V757Ffs*8). This mutation has been identified in multiple families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Sobol H et al. Cancer Res. 1996 Jul;56:3216-9; Stoppa-Lyonnet D et al. Am. J. Hum. Genet. 1997 May;60:1021-30; Liede A et al. Am. J. Hum. Genet. 2002 Sep;71:595-606; Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Rashid MU et al. BMC Cancer 2016 08;16(1):673). Of note, this alteration is also designated as 2388delG 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:
The BRCA1 p.Val757PhefsX8 variant was identified in 5 of 830 proband chromosomes (frequency: 0.006) from individuals or families with ovarian and breast cancers of French ethnicity (Berchuck_1998, Sobol_1996, Stoppa-Lyonnet_1997). The variant was also identified in dbSNP (ID: rs80357583) as “With Pathogenic allele”; in Clinvar as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Study description, by the Consortium of Investigators of Modifiers of BRCA1/2 University of Cambridge, by Ambry Genetics, by Breast Cancer Information Core; and Sharing Clinical Reports Project. The variant was also identified in Cosmic, UMD 46x with a casual classification, in BIC 10X as class 5 casual, and in ARUP Laboratories BRCA Mutations Database as definitely pathogenic. The variant was further identified in the Exome Aggregation Consortium database (August 8, 2016) in 2 of 121384 chromosomes (frequency: 0.00002) in the following populations: South Asian in 1 of 16508 chromosomes (frequency: 0.00006), European (Non-Finnish) in 1 of 66726 chromosomes (frequency: 0.00002) but was not seen in African, East Asian, European (Finnish) and Latino populations. The variant was not identified in LOVD-IARC, GeneInsight COGR, Fanconi Anemia Mutation Databases, the 1000 Genomes Project and the NHLBI GO Exome Sequencing Project. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.2269delG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 757 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. | Kowalik A | PloS one | 2018 | PMID: 30040829 |
| Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
| High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. | Rashid MU | BMC cancer | 2016 | PMID: 27553291 |
| Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. | Minucci A | Expert review of molecular diagnostics | 2015 | PMID: 26306726 |
| The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. | Kang E | Breast cancer research and treatment | 2015 | PMID: 25863477 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. | Stegel V | BMC medical genetics | 2011 | PMID: 21232165 |
| 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 |
| Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. | Liede A | American journal of human genetics | 2002 | PMID: 12181777 |
| BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. | Stoppa-Lyonnet D | American journal of human genetics | 1997 | PMID: 9150149 |
| Truncation at conserved terminal regions of BRCA1 protein is associated with highly proliferating hereditary breast cancers. | Sobol H | Cancer research | 1996 | PMID: 8764110 |
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Text-mined citations for rs80357583 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.