This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23522120, 32885271). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 37681). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Arg).
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5521A>C (p.Ser1841Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.5521A>C (p.Ser1841Arg)
Variation ID: 37681 Accession: VCV000037681.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43045749 (GRCh38) [ NCBI UCSC ] 17: 41197766 (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 Apr 1, 2014 Aug 25, 2024 Jun 14, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5521A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Ser1841Arg missense NM_001407571.1:c.5308A>C NP_001394500.1:p.Ser1770Arg missense NM_001407581.1:c.5587A>C NP_001394510.1:p.Ser1863Arg missense NM_001407582.1:c.5587A>C NP_001394511.1:p.Ser1863Arg missense NM_001407583.1:c.5584A>C NP_001394512.1:p.Ser1862Arg missense NM_001407585.1:c.5584A>C NP_001394514.1:p.Ser1862Arg missense NM_001407587.1:c.5584A>C NP_001394516.1:p.Ser1862Arg missense NM_001407590.1:c.5581A>C NP_001394519.1:p.Ser1861Arg missense NM_001407591.1:c.5581A>C NP_001394520.1:p.Ser1861Arg missense NM_001407593.1:c.5521A>C NP_001394522.1:p.Ser1841Arg missense NM_001407594.1:c.5521A>C NP_001394523.1:p.Ser1841Arg missense NM_001407596.1:c.5521A>C NP_001394525.1:p.Ser1841Arg missense NM_001407597.1:c.5521A>C NP_001394526.1:p.Ser1841Arg missense NM_001407598.1:c.5521A>C NP_001394527.1:p.Ser1841Arg missense NM_001407602.1:c.5521A>C NP_001394531.1:p.Ser1841Arg missense NM_001407603.1:c.5521A>C NP_001394532.1:p.Ser1841Arg missense NM_001407605.1:c.5521A>C NP_001394534.1:p.Ser1841Arg missense NM_001407610.1:c.5518A>C NP_001394539.1:p.Ser1840Arg missense NM_001407611.1:c.5518A>C NP_001394540.1:p.Ser1840Arg missense NM_001407612.1:c.5518A>C NP_001394541.1:p.Ser1840Arg missense NM_001407613.1:c.5518A>C NP_001394542.1:p.Ser1840Arg missense NM_001407614.1:c.5518A>C NP_001394543.1:p.Ser1840Arg missense NM_001407615.1:c.5518A>C NP_001394544.1:p.Ser1840Arg missense NM_001407616.1:c.5518A>C NP_001394545.1:p.Ser1840Arg missense NM_001407617.1:c.5518A>C NP_001394546.1:p.Ser1840Arg missense NM_001407618.1:c.5518A>C NP_001394547.1:p.Ser1840Arg missense NM_001407619.1:c.5518A>C NP_001394548.1:p.Ser1840Arg missense NM_001407620.1:c.5518A>C NP_001394549.1:p.Ser1840Arg missense NM_001407621.1:c.5518A>C NP_001394550.1:p.Ser1840Arg missense NM_001407622.1:c.5518A>C NP_001394551.1:p.Ser1840Arg missense NM_001407623.1:c.5518A>C NP_001394552.1:p.Ser1840Arg missense NM_001407624.1:c.5518A>C NP_001394553.1:p.Ser1840Arg missense NM_001407625.1:c.5518A>C NP_001394554.1:p.Ser1840Arg missense NM_001407626.1:c.5518A>C NP_001394555.1:p.Ser1840Arg missense NM_001407627.1:c.5515A>C NP_001394556.1:p.Ser1839Arg missense NM_001407628.1:c.5515A>C NP_001394557.1:p.Ser1839Arg missense NM_001407629.1:c.5515A>C NP_001394558.1:p.Ser1839Arg missense NM_001407630.1:c.5515A>C NP_001394559.1:p.Ser1839Arg missense NM_001407631.1:c.5515A>C NP_001394560.1:p.Ser1839Arg missense NM_001407632.1:c.5515A>C NP_001394561.1:p.Ser1839Arg missense NM_001407633.1:c.5515A>C NP_001394562.1:p.Ser1839Arg missense NM_001407634.1:c.5515A>C NP_001394563.1:p.Ser1839Arg missense NM_001407635.1:c.5515A>C NP_001394564.1:p.Ser1839Arg missense NM_001407636.1:c.5515A>C NP_001394565.1:p.Ser1839Arg missense NM_001407637.1:c.5515A>C NP_001394566.1:p.Ser1839Arg missense NM_001407638.1:c.5515A>C NP_001394567.1:p.Ser1839Arg missense NM_001407639.1:c.5515A>C NP_001394568.1:p.Ser1839Arg missense NM_001407640.1:c.5515A>C NP_001394569.1:p.Ser1839Arg missense NM_001407641.1:c.5515A>C NP_001394570.1:p.Ser1839Arg missense NM_001407642.1:c.5515A>C NP_001394571.1:p.Ser1839Arg missense NM_001407644.1:c.5512A>C NP_001394573.1:p.Ser1838Arg missense NM_001407645.1:c.5512A>C NP_001394574.1:p.Ser1838Arg missense NM_001407646.1:c.5509A>C NP_001394575.1:p.Ser1837Arg missense NM_001407647.1:c.5506A>C NP_001394576.1:p.Ser1836Arg missense NM_001407648.1:c.5464A>C NP_001394577.1:p.Ser1822Arg missense NM_001407649.1:c.5461A>C NP_001394578.1:p.Ser1821Arg missense NM_001407652.1:c.5443A>C NP_001394581.1:p.Ser1815Arg missense NM_001407653.1:c.5443A>C NP_001394582.1:p.Ser1815Arg missense NM_001407654.1:c.5443A>C NP_001394583.1:p.Ser1815Arg missense NM_001407655.1:c.5443A>C NP_001394584.1:p.Ser1815Arg missense NM_001407656.1:c.5440A>C NP_001394585.1:p.Ser1814Arg missense NM_001407657.1:c.5440A>C NP_001394586.1:p.Ser1814Arg missense NM_001407658.1:c.5440A>C NP_001394587.1:p.Ser1814Arg missense NM_001407659.1:c.5437A>C NP_001394588.1:p.Ser1813Arg missense NM_001407660.1:c.5437A>C NP_001394589.1:p.Ser1813Arg missense NM_001407661.1:c.5437A>C NP_001394590.1:p.Ser1813Arg missense NM_001407662.1:c.5437A>C NP_001394591.1:p.Ser1813Arg missense NM_001407663.1:c.5437A>C NP_001394592.1:p.Ser1813Arg missense NM_001407664.1:c.5398A>C NP_001394593.1:p.Ser1800Arg missense NM_001407665.1:c.5398A>C NP_001394594.1:p.Ser1800Arg missense NM_001407666.1:c.5398A>C NP_001394595.1:p.Ser1800Arg missense NM_001407667.1:c.5398A>C NP_001394596.1:p.Ser1800Arg missense NM_001407668.1:c.5398A>C NP_001394597.1:p.Ser1800Arg missense NM_001407669.1:c.5398A>C NP_001394598.1:p.Ser1800Arg missense NM_001407670.1:c.5395A>C NP_001394599.1:p.Ser1799Arg missense NM_001407671.1:c.5395A>C NP_001394600.1:p.Ser1799Arg missense NM_001407672.1:c.5395A>C NP_001394601.1:p.Ser1799Arg missense NM_001407673.1:c.5395A>C NP_001394602.1:p.Ser1799Arg missense NM_001407674.1:c.5395A>C NP_001394603.1:p.Ser1799Arg missense NM_001407675.1:c.5395A>C NP_001394604.1:p.Ser1799Arg missense NM_001407676.1:c.5395A>C NP_001394605.1:p.Ser1799Arg missense NM_001407677.1:c.5395A>C NP_001394606.1:p.Ser1799Arg missense NM_001407678.1:c.5395A>C NP_001394607.1:p.Ser1799Arg missense NM_001407679.1:c.5395A>C NP_001394608.1:p.Ser1799Arg missense NM_001407680.1:c.5395A>C NP_001394609.1:p.Ser1799Arg missense NM_001407681.1:c.5392A>C NP_001394610.1:p.Ser1798Arg missense NM_001407682.1:c.5392A>C NP_001394611.1:p.Ser1798Arg missense NM_001407683.1:c.5392A>C NP_001394612.1:p.Ser1798Arg missense NM_001407684.1:c.5392A>C NP_001394613.1:p.Ser1798Arg missense NM_001407685.1:c.5392A>C NP_001394614.1:p.Ser1798Arg missense NM_001407686.1:c.5392A>C NP_001394615.1:p.Ser1798Arg missense NM_001407687.1:c.5392A>C NP_001394616.1:p.Ser1798Arg missense NM_001407688.1:c.5392A>C NP_001394617.1:p.Ser1798Arg missense NM_001407689.1:c.5392A>C NP_001394618.1:p.Ser1798Arg missense NM_001407690.1:c.5389A>C NP_001394619.1:p.Ser1797Arg missense NM_001407691.1:c.5389A>C NP_001394620.1:p.Ser1797Arg missense NM_001407692.1:c.5380A>C NP_001394621.1:p.Ser1794Arg missense NM_001407694.1:c.5380A>C NP_001394623.1:p.Ser1794Arg missense NM_001407695.1:c.5380A>C NP_001394624.1:p.Ser1794Arg missense NM_001407696.1:c.5380A>C NP_001394625.1:p.Ser1794Arg missense NM_001407697.1:c.5380A>C NP_001394626.1:p.Ser1794Arg missense NM_001407698.1:c.5380A>C NP_001394627.1:p.Ser1794Arg missense NM_001407724.1:c.5380A>C NP_001394653.1:p.Ser1794Arg missense NM_001407725.1:c.5380A>C NP_001394654.1:p.Ser1794Arg missense NM_001407726.1:c.5380A>C NP_001394655.1:p.Ser1794Arg missense NM_001407727.1:c.5380A>C NP_001394656.1:p.Ser1794Arg missense NM_001407728.1:c.5380A>C NP_001394657.1:p.Ser1794Arg missense NM_001407729.1:c.5380A>C NP_001394658.1:p.Ser1794Arg missense NM_001407730.1:c.5380A>C NP_001394659.1:p.Ser1794Arg missense NM_001407731.1:c.5380A>C NP_001394660.1:p.Ser1794Arg missense NM_001407732.1:c.5377A>C NP_001394661.1:p.Ser1793Arg missense NM_001407733.1:c.5377A>C NP_001394662.1:p.Ser1793Arg missense NM_001407734.1:c.5377A>C NP_001394663.1:p.Ser1793Arg missense NM_001407735.1:c.5377A>C NP_001394664.1:p.Ser1793Arg missense NM_001407736.1:c.5377A>C NP_001394665.1:p.Ser1793Arg missense NM_001407737.1:c.5377A>C NP_001394666.1:p.Ser1793Arg missense NM_001407738.1:c.5377A>C NP_001394667.1:p.Ser1793Arg missense NM_001407739.1:c.5377A>C NP_001394668.1:p.Ser1793Arg missense NM_001407740.1:c.5377A>C NP_001394669.1:p.Ser1793Arg missense NM_001407741.1:c.5377A>C NP_001394670.1:p.Ser1793Arg missense NM_001407742.1:c.5377A>C NP_001394671.1:p.Ser1793Arg missense NM_001407743.1:c.5377A>C NP_001394672.1:p.Ser1793Arg missense NM_001407744.1:c.5377A>C NP_001394673.1:p.Ser1793Arg missense NM_001407745.1:c.5377A>C NP_001394674.1:p.Ser1793Arg missense NM_001407746.1:c.5377A>C NP_001394675.1:p.Ser1793Arg missense NM_001407747.1:c.5377A>C NP_001394676.1:p.Ser1793Arg missense NM_001407748.1:c.5377A>C NP_001394677.1:p.Ser1793Arg missense NM_001407749.1:c.5377A>C NP_001394678.1:p.Ser1793Arg missense NM_001407750.1:c.5377A>C NP_001394679.1:p.Ser1793Arg missense NM_001407751.1:c.5377A>C NP_001394680.1:p.Ser1793Arg missense NM_001407752.1:c.5377A>C NP_001394681.1:p.Ser1793Arg missense NM_001407838.1:c.5374A>C NP_001394767.1:p.Ser1792Arg missense NM_001407839.1:c.5374A>C NP_001394768.1:p.Ser1792Arg missense NM_001407841.1:c.5374A>C NP_001394770.1:p.Ser1792Arg missense NM_001407842.1:c.5374A>C NP_001394771.1:p.Ser1792Arg missense NM_001407843.1:c.5374A>C NP_001394772.1:p.Ser1792Arg missense NM_001407844.1:c.5374A>C NP_001394773.1:p.Ser1792Arg missense NM_001407845.1:c.5374A>C NP_001394774.1:p.Ser1792Arg missense NM_001407846.1:c.5374A>C NP_001394775.1:p.Ser1792Arg missense NM_001407847.1:c.5374A>C NP_001394776.1:p.Ser1792Arg missense NM_001407848.1:c.5374A>C NP_001394777.1:p.Ser1792Arg missense NM_001407849.1:c.5374A>C NP_001394778.1:p.Ser1792Arg missense NM_001407850.1:c.5374A>C NP_001394779.1:p.Ser1792Arg missense NM_001407851.1:c.5374A>C NP_001394780.1:p.Ser1792Arg missense NM_001407852.1:c.5374A>C NP_001394781.1:p.Ser1792Arg missense NM_001407853.1:c.5374A>C NP_001394782.1:p.Ser1792Arg missense NM_001407854.1:c.*35A>C NM_001407858.1:c.*35A>C NM_001407859.1:c.*35A>C NM_001407860.1:c.*35A>C NM_001407861.1:c.*35A>C NM_001407862.1:c.5320A>C NP_001394791.1:p.Ser1774Arg missense NM_001407863.1:c.5317A>C NP_001394792.1:p.Ser1773Arg missense NM_001407874.1:c.5314A>C NP_001394803.1:p.Ser1772Arg missense NM_001407875.1:c.5314A>C NP_001394804.1:p.Ser1772Arg missense NM_001407879.1:c.5311A>C NP_001394808.1:p.Ser1771Arg missense NM_001407881.1:c.5311A>C NP_001394810.1:p.Ser1771Arg missense NM_001407882.1:c.5311A>C NP_001394811.1:p.Ser1771Arg missense NM_001407884.1:c.5311A>C NP_001394813.1:p.Ser1771Arg missense NM_001407885.1:c.5311A>C NP_001394814.1:p.Ser1771Arg missense NM_001407886.1:c.5311A>C NP_001394815.1:p.Ser1771Arg missense NM_001407887.1:c.5311A>C NP_001394816.1:p.Ser1771Arg missense NM_001407889.1:c.5311A>C NP_001394818.1:p.Ser1771Arg missense NM_001407894.1:c.5308A>C NP_001394823.1:p.Ser1770Arg missense NM_001407895.1:c.5308A>C NP_001394824.1:p.Ser1770Arg missense NM_001407896.1:c.5308A>C NP_001394825.1:p.Ser1770Arg missense NM_001407897.1:c.5308A>C NP_001394826.1:p.Ser1770Arg missense NM_001407898.1:c.5308A>C NP_001394827.1:p.Ser1770Arg missense NM_001407899.1:c.5308A>C NP_001394828.1:p.Ser1770Arg missense NM_001407900.1:c.5308A>C NP_001394829.1:p.Ser1770Arg missense NM_001407902.1:c.5308A>C NP_001394831.1:p.Ser1770Arg missense NM_001407904.1:c.5308A>C NP_001394833.1:p.Ser1770Arg missense NM_001407906.1:c.5308A>C NP_001394835.1:p.Ser1770Arg missense NM_001407907.1:c.5308A>C NP_001394836.1:p.Ser1770Arg missense NM_001407908.1:c.5308A>C NP_001394837.1:p.Ser1770Arg missense NM_001407909.1:c.5308A>C NP_001394838.1:p.Ser1770Arg missense NM_001407910.1:c.5308A>C NP_001394839.1:p.Ser1770Arg missense NM_001407915.1:c.5305A>C NP_001394844.1:p.Ser1769Arg missense NM_001407916.1:c.5305A>C NP_001394845.1:p.Ser1769Arg missense NM_001407917.1:c.5305A>C NP_001394846.1:p.Ser1769Arg missense NM_001407918.1:c.5305A>C NP_001394847.1:p.Ser1769Arg missense NM_001407919.1:c.5269A>C NP_001394848.1:p.Ser1757Arg missense NM_001407920.1:c.5257A>C NP_001394849.1:p.Ser1753Arg missense NM_001407921.1:c.5257A>C NP_001394850.1:p.Ser1753Arg missense NM_001407922.1:c.5257A>C NP_001394851.1:p.Ser1753Arg missense NM_001407923.1:c.5257A>C NP_001394852.1:p.Ser1753Arg missense NM_001407924.1:c.5257A>C NP_001394853.1:p.Ser1753Arg missense NM_001407925.1:c.5257A>C NP_001394854.1:p.Ser1753Arg missense NM_001407926.1:c.5257A>C NP_001394855.1:p.Ser1753Arg missense NM_001407927.1:c.5254A>C NP_001394856.1:p.Ser1752Arg missense NM_001407928.1:c.5254A>C NP_001394857.1:p.Ser1752Arg missense NM_001407929.1:c.5254A>C NP_001394858.1:p.Ser1752Arg missense NM_001407930.1:c.5254A>C NP_001394859.1:p.Ser1752Arg missense NM_001407931.1:c.5254A>C NP_001394860.1:p.Ser1752Arg missense NM_001407932.1:c.5254A>C NP_001394861.1:p.Ser1752Arg missense NM_001407933.1:c.5254A>C NP_001394862.1:p.Ser1752Arg missense NM_001407934.1:c.5251A>C NP_001394863.1:p.Ser1751Arg missense NM_001407935.1:c.5251A>C NP_001394864.1:p.Ser1751Arg missense NM_001407936.1:c.5251A>C NP_001394865.1:p.Ser1751Arg missense NM_001407937.1:c.*35A>C NM_001407938.1:c.*35A>C NM_001407939.1:c.*35A>C NM_001407940.1:c.*35A>C NM_001407941.1:c.*35A>C NM_001407942.1:c.*35A>C NM_001407943.1:c.*35A>C NM_001407944.1:c.*35A>C NM_001407945.1:c.*35A>C NM_001407946.1:c.5188A>C NP_001394875.1:p.Ser1730Arg missense NM_001407947.1:c.5188A>C NP_001394876.1:p.Ser1730Arg missense NM_001407948.1:c.5188A>C NP_001394877.1:p.Ser1730Arg missense NM_001407949.1:c.5188A>C NP_001394878.1:p.Ser1730Arg missense NM_001407950.1:c.5185A>C NP_001394879.1:p.Ser1729Arg missense NM_001407951.1:c.5185A>C NP_001394880.1:p.Ser1729Arg missense NM_001407952.1:c.5185A>C NP_001394881.1:p.Ser1729Arg missense NM_001407953.1:c.5185A>C NP_001394882.1:p.Ser1729Arg missense NM_001407954.1:c.5185A>C NP_001394883.1:p.Ser1729Arg missense NM_001407955.1:c.5185A>C NP_001394884.1:p.Ser1729Arg missense NM_001407956.1:c.5182A>C NP_001394885.1:p.Ser1728Arg missense NM_001407957.1:c.5182A>C NP_001394886.1:p.Ser1728Arg missense NM_001407958.1:c.5182A>C NP_001394887.1:p.Ser1728Arg missense NM_001407959.1:c.5140A>C NP_001394888.1:p.Ser1714Arg missense NM_001407960.1:c.5137A>C NP_001394889.1:p.Ser1713Arg missense NM_001407962.1:c.5137A>C NP_001394891.1:p.Ser1713Arg missense NM_001407963.1:c.5134A>C NP_001394892.1:p.Ser1712Arg missense NM_001407964.1:c.5059A>C NP_001394893.1:p.Ser1687Arg missense NM_001407965.1:c.5014A>C NP_001394894.1:p.Ser1672Arg missense NM_001407966.1:c.4633A>C NP_001394895.1:p.Ser1545Arg missense NM_001407967.1:c.4630A>C NP_001394896.1:p.Ser1544Arg missense NM_001407968.1:c.2917A>C NP_001394897.1:p.Ser973Arg missense NM_001407969.1:c.2914A>C NP_001394898.1:p.Ser972Arg missense NM_001407970.1:c.2278A>C NP_001394899.1:p.Ser760Arg missense NM_001407971.1:c.2278A>C NP_001394900.1:p.Ser760Arg missense NM_001407972.1:c.2275A>C NP_001394901.1:p.Ser759Arg missense NM_001407973.1:c.2212A>C NP_001394902.1:p.Ser738Arg missense NM_001407974.1:c.2212A>C NP_001394903.1:p.Ser738Arg missense NM_001407975.1:c.2212A>C NP_001394904.1:p.Ser738Arg missense NM_001407976.1:c.2212A>C NP_001394905.1:p.Ser738Arg missense NM_001407977.1:c.2212A>C NP_001394906.1:p.Ser738Arg missense NM_001407978.1:c.2212A>C NP_001394907.1:p.Ser738Arg missense NM_001407979.1:c.2209A>C NP_001394908.1:p.Ser737Arg missense NM_001407980.1:c.2209A>C NP_001394909.1:p.Ser737Arg missense NM_001407981.1:c.2209A>C NP_001394910.1:p.Ser737Arg missense NM_001407982.1:c.2209A>C NP_001394911.1:p.Ser737Arg missense NM_001407983.1:c.2209A>C NP_001394912.1:p.Ser737Arg missense NM_001407984.1:c.2209A>C NP_001394913.1:p.Ser737Arg missense NM_001407985.1:c.2209A>C NP_001394914.1:p.Ser737Arg missense NM_001407986.1:c.2209A>C NP_001394915.1:p.Ser737Arg missense NM_001407990.1:c.2209A>C NP_001394919.1:p.Ser737Arg missense NM_001407991.1:c.2209A>C NP_001394920.1:p.Ser737Arg missense NM_001407992.1:c.2209A>C NP_001394921.1:p.Ser737Arg missense NM_001407993.1:c.2209A>C NP_001394922.1:p.Ser737Arg missense NM_001408392.1:c.2206A>C NP_001395321.1:p.Ser736Arg missense NM_001408396.1:c.2206A>C NP_001395325.1:p.Ser736Arg missense NM_001408397.1:c.2206A>C NP_001395326.1:p.Ser736Arg missense NM_001408398.1:c.2206A>C NP_001395327.1:p.Ser736Arg missense NM_001408399.1:c.2206A>C NP_001395328.1:p.Ser736Arg missense NM_001408400.1:c.2206A>C NP_001395329.1:p.Ser736Arg missense NM_001408401.1:c.2206A>C NP_001395330.1:p.Ser736Arg missense NM_001408402.1:c.2206A>C NP_001395331.1:p.Ser736Arg missense NM_001408403.1:c.2206A>C NP_001395332.1:p.Ser736Arg missense NM_001408404.1:c.2206A>C NP_001395333.1:p.Ser736Arg missense NM_001408406.1:c.2203A>C NP_001395335.1:p.Ser735Arg missense NM_001408407.1:c.2203A>C NP_001395336.1:p.Ser735Arg missense NM_001408408.1:c.2203A>C NP_001395337.1:p.Ser735Arg missense NM_001408409.1:c.2200A>C NP_001395338.1:p.Ser734Arg missense NM_001408410.1:c.2137A>C NP_001395339.1:p.Ser713Arg missense NM_001408411.1:c.2134A>C NP_001395340.1:p.Ser712Arg missense NM_001408412.1:c.2131A>C NP_001395341.1:p.Ser711Arg missense NM_001408413.1:c.2131A>C NP_001395342.1:p.Ser711Arg missense NM_001408414.1:c.2131A>C NP_001395343.1:p.Ser711Arg missense NM_001408415.1:c.2131A>C NP_001395344.1:p.Ser711Arg missense NM_001408416.1:c.2131A>C NP_001395345.1:p.Ser711Arg missense NM_001408418.1:c.2095A>C NP_001395347.1:p.Ser699Arg missense NM_001408419.1:c.2095A>C NP_001395348.1:p.Ser699Arg missense NM_001408420.1:c.2095A>C NP_001395349.1:p.Ser699Arg missense NM_001408421.1:c.2092A>C NP_001395350.1:p.Ser698Arg missense NM_001408422.1:c.2092A>C NP_001395351.1:p.Ser698Arg missense NM_001408423.1:c.2092A>C NP_001395352.1:p.Ser698Arg missense NM_001408424.1:c.2092A>C NP_001395353.1:p.Ser698Arg missense NM_001408425.1:c.2089A>C NP_001395354.1:p.Ser697Arg missense NM_001408426.1:c.2089A>C NP_001395355.1:p.Ser697Arg missense NM_001408427.1:c.2089A>C NP_001395356.1:p.Ser697Arg missense NM_001408428.1:c.2089A>C NP_001395357.1:p.Ser697Arg missense NM_001408429.1:c.2089A>C NP_001395358.1:p.Ser697Arg missense NM_001408430.1:c.2089A>C NP_001395359.1:p.Ser697Arg missense NM_001408431.1:c.2089A>C NP_001395360.1:p.Ser697Arg missense NM_001408432.1:c.2086A>C NP_001395361.1:p.Ser696Arg missense NM_001408433.1:c.2086A>C NP_001395362.1:p.Ser696Arg missense NM_001408434.1:c.2086A>C NP_001395363.1:p.Ser696Arg missense NM_001408435.1:c.2086A>C NP_001395364.1:p.Ser696Arg missense NM_001408436.1:c.2086A>C NP_001395365.1:p.Ser696Arg missense NM_001408437.1:c.2086A>C NP_001395366.1:p.Ser696Arg missense NM_001408438.1:c.2086A>C NP_001395367.1:p.Ser696Arg missense NM_001408439.1:c.2086A>C NP_001395368.1:p.Ser696Arg missense NM_001408440.1:c.2086A>C NP_001395369.1:p.Ser696Arg missense NM_001408441.1:c.2086A>C NP_001395370.1:p.Ser696Arg missense NM_001408442.1:c.2086A>C NP_001395371.1:p.Ser696Arg missense NM_001408443.1:c.2086A>C NP_001395372.1:p.Ser696Arg missense NM_001408444.1:c.2086A>C NP_001395373.1:p.Ser696Arg missense NM_001408445.1:c.2083A>C NP_001395374.1:p.Ser695Arg missense NM_001408446.1:c.2083A>C NP_001395375.1:p.Ser695Arg missense NM_001408447.1:c.2083A>C NP_001395376.1:p.Ser695Arg missense NM_001408448.1:c.2083A>C NP_001395377.1:p.Ser695Arg missense NM_001408450.1:c.2083A>C NP_001395379.1:p.Ser695Arg missense NM_001408451.1:c.2077A>C NP_001395380.1:p.Ser693Arg missense NM_001408452.1:c.2071A>C NP_001395381.1:p.Ser691Arg missense NM_001408453.1:c.2071A>C NP_001395382.1:p.Ser691Arg missense NM_001408454.1:c.2071A>C NP_001395383.1:p.Ser691Arg missense NM_001408455.1:c.2071A>C NP_001395384.1:p.Ser691Arg missense NM_001408456.1:c.2071A>C NP_001395385.1:p.Ser691Arg missense NM_001408457.1:c.2071A>C NP_001395386.1:p.Ser691Arg missense NM_001408458.1:c.2068A>C NP_001395387.1:p.Ser690Arg missense NM_001408459.1:c.2068A>C NP_001395388.1:p.Ser690Arg missense NM_001408460.1:c.2068A>C NP_001395389.1:p.Ser690Arg missense NM_001408461.1:c.2068A>C NP_001395390.1:p.Ser690Arg missense NM_001408462.1:c.2068A>C NP_001395391.1:p.Ser690Arg missense NM_001408463.1:c.2068A>C NP_001395392.1:p.Ser690Arg missense NM_001408464.1:c.2068A>C NP_001395393.1:p.Ser690Arg missense NM_001408465.1:c.2068A>C NP_001395394.1:p.Ser690Arg missense NM_001408466.1:c.2068A>C NP_001395395.1:p.Ser690Arg missense NM_001408467.1:c.2068A>C NP_001395396.1:p.Ser690Arg missense NM_001408468.1:c.2065A>C NP_001395397.1:p.Ser689Arg missense NM_001408469.1:c.2065A>C NP_001395398.1:p.Ser689Arg missense NM_001408470.1:c.2065A>C NP_001395399.1:p.Ser689Arg missense NM_001408472.1:c.*35A>C NM_001408473.1:c.*35A>C NM_001408474.1:c.2011A>C NP_001395403.1:p.Ser671Arg missense NM_001408475.1:c.2008A>C NP_001395404.1:p.Ser670Arg missense NM_001408476.1:c.2008A>C NP_001395405.1:p.Ser670Arg missense NM_001408478.1:c.2002A>C NP_001395407.1:p.Ser668Arg missense NM_001408479.1:c.2002A>C NP_001395408.1:p.Ser668Arg missense NM_001408480.1:c.2002A>C NP_001395409.1:p.Ser668Arg missense NM_001408481.1:c.1999A>C NP_001395410.1:p.Ser667Arg missense NM_001408482.1:c.1999A>C NP_001395411.1:p.Ser667Arg missense NM_001408483.1:c.1999A>C NP_001395412.1:p.Ser667Arg missense NM_001408484.1:c.1999A>C NP_001395413.1:p.Ser667Arg missense NM_001408485.1:c.1999A>C NP_001395414.1:p.Ser667Arg missense NM_001408489.1:c.1999A>C NP_001395418.1:p.Ser667Arg missense NM_001408490.1:c.1999A>C NP_001395419.1:p.Ser667Arg missense NM_001408491.1:c.1999A>C NP_001395420.1:p.Ser667Arg missense NM_001408492.1:c.1996A>C NP_001395421.1:p.Ser666Arg missense NM_001408493.1:c.1996A>C NP_001395422.1:p.Ser666Arg missense NM_001408494.1:c.1972A>C NP_001395423.1:p.Ser658Arg missense NM_001408495.1:c.1966A>C NP_001395424.1:p.Ser656Arg missense NM_001408496.1:c.1948A>C NP_001395425.1:p.Ser650Arg missense NM_001408497.1:c.1948A>C NP_001395426.1:p.Ser650Arg missense NM_001408498.1:c.1948A>C NP_001395427.1:p.Ser650Arg missense NM_001408499.1:c.1948A>C NP_001395428.1:p.Ser650Arg missense NM_001408500.1:c.1948A>C NP_001395429.1:p.Ser650Arg missense NM_001408501.1:c.1948A>C NP_001395430.1:p.Ser650Arg missense NM_001408502.1:c.1945A>C NP_001395431.1:p.Ser649Arg missense NM_001408503.1:c.1945A>C NP_001395432.1:p.Ser649Arg missense NM_001408504.1:c.1945A>C NP_001395433.1:p.Ser649Arg missense NM_001408505.1:c.1942A>C NP_001395434.1:p.Ser648Arg missense NM_001408506.1:c.1885A>C NP_001395435.1:p.Ser629Arg missense NM_001408507.1:c.1882A>C NP_001395436.1:p.Ser628Arg missense NM_001408508.1:c.1873A>C NP_001395437.1:p.Ser625Arg missense NM_001408509.1:c.1870A>C NP_001395438.1:p.Ser624Arg missense NM_001408510.1:c.1831A>C NP_001395439.1:p.Ser611Arg missense NM_001408511.1:c.1828A>C NP_001395440.1:p.Ser610Arg missense NM_001408512.1:c.1708A>C NP_001395441.1:p.Ser570Arg missense NM_001408513.1:c.1681A>C NP_001395442.1:p.Ser561Arg missense NM_001408514.1:c.1285A>C NP_001395443.1:p.Ser429Arg missense NM_007297.4:c.5380A>C NP_009228.2:p.Ser1794Arg missense NM_007298.4:c.2209A>C NP_009229.2:p.Ser737Arg missense NM_007299.4:c.*35A>C 3 prime UTR NM_007300.4:c.5584A>C NP_009231.2:p.Ser1862Arg missense NM_007304.2:c.2209A>C NP_009235.2:p.Ser737Arg missense NR_027676.2:n.5698A>C non-coding transcript variant NC_000017.11:g.43045749T>G NC_000017.10:g.41197766T>G NG_005905.2:g.172235A>C LRG_292:g.172235A>C LRG_292t1:c.5521A>C LRG_292p1:p.Ser1841Arg U14680.1:n.5640A>C - Protein change
- S1841R, S1862R, S737R, S1794R, S1544R, S1687R, S1714R, S1770R, S1773R, S1774R, S1840R, S1863R, S610R, S611R, S628R, S656R, S670R, S699R, S712R, S734R, S1545R, S1712R, S1728R, S1753R, S1757R, S1772R, S1793R, S1797R, S1814R, S1822R, S1836R, S1837R, S625R, S648R, S649R, S668R, S671R, S695R, S696R, S698R, S713R, S736R, S760R, S735R, S759R, S1672R, S1713R, S1730R, S1751R, S1771R, S1792R, S1800R, S1838R, S429R, S561R, S570R, S650R, S666R, S693R, S697R, S973R, S1729R, S1752R, S1769R, S1798R, S1799R, S1813R, S1815R, S1821R, S1839R, S1861R, S624R, S629R, S658R, S667R, S689R, S690R, S691R, S711R, S738R, S972R
- Other names
-
5640A>C
- Canonical SPDI
- NC_000017.11:43045748:T:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
functionally_abnormal; Sequence Ontology [ SO:0002218]The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5521A>C, a MISSENSE variant, produced a function score of -1.72, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. [submitted by Brotman Baty Institute, University of Washington]
-
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 |
13044 | 14850 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
no assertion criteria provided
|
Jan 17, 2024 | RCV000031262.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV000735509.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2023 | RCV002513284.3 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Jan 31, 2014 | RCV000496641.2 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Apr 14, 2023 | RCV000501320.5 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 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: SCV003441864.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23522120, 32885271). It has also been observed to segregate with disease … (more)
This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23522120, 32885271). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 37681). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Arg). (less)
|
|
|
Likely pathogenic
(Apr 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199693.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Uncertain significance
(Nov 25, 2004)
|
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: SCV000145564.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European, French Canadian
|
|
|
Uncertain significance
(May 21, 2010)
|
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: SCV000053866.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014 |
|
|
|
Uncertain significance
(Jan 31, 2014)
|
no assertion criteria provided
Method: research
|
not specified
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: SCV000587519.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
|
|
|
Likely 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: SCV000591638.2 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
The BRCA1 p.Ser1841Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was … (more)
The BRCA1 p.Ser1841Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs80357299) as “with likely pathogenic allele”, ClinVar (classified as uncertain significance by BIC, SCRP and Women's College Hospital and likely pathogenic by Lady Davis Institute for Medical Research) and LOVD 3.0 (observed 1x). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 protein folding, binding and transactivational activity (Lee 2010). Additionally, the variant co-segregated with disease in a family; it was identified in a patient with ovarian cancer, and segregated in 3 family members, including one prostate cancer and two breast cancer cases (Zhang 2013). The p.Ser1841 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 17, 2024)
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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: SCV004243902.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863647.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
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not provided
(-)
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no classification provided
Method: in vitro
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Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
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Brotman Baty Institute, University of Washington
Accession: SCV001243498.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.72209824493603
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Comment:
Comment:
The BRCA1 p.Ser1841Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs80357299) as “with likely pathogenic allele”, ClinVar (classified as uncertain significance by BIC, SCRP and Women's College Hospital and likely pathogenic by Lady Davis Institute for Medical Research) and LOVD 3.0 (observed 1x). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 protein folding, binding and transactivational activity (Lee 2010). Additionally, the variant co-segregated with disease in a family; it was identified in a patient with ovarian cancer, and segregated in 3 family members, including one prostate cancer and two breast cancer cases (Zhang 2013). The p.Ser1841 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_abnormal
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Method citation(s):
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Brotman Baty Institute, University of Washington
Accession: SCV001243498.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5521A>C, a MISSENSE variant, produced a function score of -1.72, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5521A>C, a MISSENSE variant, produced a function score of -1.72, corresponding to a functional classification of LOSS_OF_FUNCTION. SGE function score ranges for classification are as follows: ‘functional’, score > -0.748; ‘intermediate’, -0.748 > score > -1.328; ‘non-functional’, score < -1.328. The median synonymous SNV scored 0.0 and the median nonsense SNV scored -2.12. (less)
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Comment:
This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 23522120, 32885271). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 30209399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 37681). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1841 of the BRCA1 protein (p.Ser1841Arg).
Comment:
The BRCA1 p.Ser1841Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (rs80357299) as “with likely pathogenic allele”, ClinVar (classified as uncertain significance by BIC, SCRP and Women's College Hospital and likely pathogenic by Lady Davis Institute for Medical Research) and LOVD 3.0 (observed 1x). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In vitro expression of the variant had a demonstrable effect on BRCA1 protein folding, binding and transactivational activity (Lee 2010). Additionally, the variant co-segregated with disease in a family; it was identified in a patient with ovarian cancer, and segregated in 3 family members, including one prostate cancer and two breast cancer cases (Zhang 2013). The p.Ser1841 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient. | Zhang J | BMC cancer | 2013 | PMID: 23522120 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
Text-mined citations for rs80357299 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.