In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30765603, 28781887, 30209399, 16786532, 20378548, 16969499, 17005433, 25748678, 30257991). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822). ClinVar contains an entry for this variant (Variation ID: 55613). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1841 of the BRCA1 protein (p.Ser1841Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine.
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.5522G>A (p.Ser1841Asn)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007294.4(BRCA1):c.5522G>A (p.Ser1841Asn)
Variation ID: 55613 Accession: VCV000055613.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43045748 (GRCh38) [ NCBI UCSC ] 17: 41197765 (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 May 1, 2024 Aug 25, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.5522G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Ser1841Asn missense NM_001407571.1:c.5309G>A NP_001394500.1:p.Ser1770Asn missense NM_001407581.1:c.5588G>A NP_001394510.1:p.Ser1863Asn missense NM_001407582.1:c.5588G>A NP_001394511.1:p.Ser1863Asn missense NM_001407583.1:c.5585G>A NP_001394512.1:p.Ser1862Asn missense NM_001407585.1:c.5585G>A NP_001394514.1:p.Ser1862Asn missense NM_001407587.1:c.5585G>A NP_001394516.1:p.Ser1862Asn missense NM_001407590.1:c.5582G>A NP_001394519.1:p.Ser1861Asn missense NM_001407591.1:c.5582G>A NP_001394520.1:p.Ser1861Asn missense NM_001407593.1:c.5522G>A NP_001394522.1:p.Ser1841Asn missense NM_001407594.1:c.5522G>A NP_001394523.1:p.Ser1841Asn missense NM_001407596.1:c.5522G>A NP_001394525.1:p.Ser1841Asn missense NM_001407597.1:c.5522G>A NP_001394526.1:p.Ser1841Asn missense NM_001407598.1:c.5522G>A NP_001394527.1:p.Ser1841Asn missense NM_001407602.1:c.5522G>A NP_001394531.1:p.Ser1841Asn missense NM_001407603.1:c.5522G>A NP_001394532.1:p.Ser1841Asn missense NM_001407605.1:c.5522G>A NP_001394534.1:p.Ser1841Asn missense NM_001407610.1:c.5519G>A NP_001394539.1:p.Ser1840Asn missense NM_001407611.1:c.5519G>A NP_001394540.1:p.Ser1840Asn missense NM_001407612.1:c.5519G>A NP_001394541.1:p.Ser1840Asn missense NM_001407613.1:c.5519G>A NP_001394542.1:p.Ser1840Asn missense NM_001407614.1:c.5519G>A NP_001394543.1:p.Ser1840Asn missense NM_001407615.1:c.5519G>A NP_001394544.1:p.Ser1840Asn missense NM_001407616.1:c.5519G>A NP_001394545.1:p.Ser1840Asn missense NM_001407617.1:c.5519G>A NP_001394546.1:p.Ser1840Asn missense NM_001407618.1:c.5519G>A NP_001394547.1:p.Ser1840Asn missense NM_001407619.1:c.5519G>A NP_001394548.1:p.Ser1840Asn missense NM_001407620.1:c.5519G>A NP_001394549.1:p.Ser1840Asn missense NM_001407621.1:c.5519G>A NP_001394550.1:p.Ser1840Asn missense NM_001407622.1:c.5519G>A NP_001394551.1:p.Ser1840Asn missense NM_001407623.1:c.5519G>A NP_001394552.1:p.Ser1840Asn missense NM_001407624.1:c.5519G>A NP_001394553.1:p.Ser1840Asn missense NM_001407625.1:c.5519G>A NP_001394554.1:p.Ser1840Asn missense NM_001407626.1:c.5519G>A NP_001394555.1:p.Ser1840Asn missense NM_001407627.1:c.5516G>A NP_001394556.1:p.Ser1839Asn missense NM_001407628.1:c.5516G>A NP_001394557.1:p.Ser1839Asn missense NM_001407629.1:c.5516G>A NP_001394558.1:p.Ser1839Asn missense NM_001407630.1:c.5516G>A NP_001394559.1:p.Ser1839Asn missense NM_001407631.1:c.5516G>A NP_001394560.1:p.Ser1839Asn missense NM_001407632.1:c.5516G>A NP_001394561.1:p.Ser1839Asn missense NM_001407633.1:c.5516G>A NP_001394562.1:p.Ser1839Asn missense NM_001407634.1:c.5516G>A NP_001394563.1:p.Ser1839Asn missense NM_001407635.1:c.5516G>A NP_001394564.1:p.Ser1839Asn missense NM_001407636.1:c.5516G>A NP_001394565.1:p.Ser1839Asn missense NM_001407637.1:c.5516G>A NP_001394566.1:p.Ser1839Asn missense NM_001407638.1:c.5516G>A NP_001394567.1:p.Ser1839Asn missense NM_001407639.1:c.5516G>A NP_001394568.1:p.Ser1839Asn missense NM_001407640.1:c.5516G>A NP_001394569.1:p.Ser1839Asn missense NM_001407641.1:c.5516G>A NP_001394570.1:p.Ser1839Asn missense NM_001407642.1:c.5516G>A NP_001394571.1:p.Ser1839Asn missense NM_001407644.1:c.5513G>A NP_001394573.1:p.Ser1838Asn missense NM_001407645.1:c.5513G>A NP_001394574.1:p.Ser1838Asn missense NM_001407646.1:c.5510G>A NP_001394575.1:p.Ser1837Asn missense NM_001407647.1:c.5507G>A NP_001394576.1:p.Ser1836Asn missense NM_001407648.1:c.5465G>A NP_001394577.1:p.Ser1822Asn missense NM_001407649.1:c.5462G>A NP_001394578.1:p.Ser1821Asn missense NM_001407652.1:c.5444G>A NP_001394581.1:p.Ser1815Asn missense NM_001407653.1:c.5444G>A NP_001394582.1:p.Ser1815Asn missense NM_001407654.1:c.5444G>A NP_001394583.1:p.Ser1815Asn missense NM_001407655.1:c.5444G>A NP_001394584.1:p.Ser1815Asn missense NM_001407656.1:c.5441G>A NP_001394585.1:p.Ser1814Asn missense NM_001407657.1:c.5441G>A NP_001394586.1:p.Ser1814Asn missense NM_001407658.1:c.5441G>A NP_001394587.1:p.Ser1814Asn missense NM_001407659.1:c.5438G>A NP_001394588.1:p.Ser1813Asn missense NM_001407660.1:c.5438G>A NP_001394589.1:p.Ser1813Asn missense NM_001407661.1:c.5438G>A NP_001394590.1:p.Ser1813Asn missense NM_001407662.1:c.5438G>A NP_001394591.1:p.Ser1813Asn missense NM_001407663.1:c.5438G>A NP_001394592.1:p.Ser1813Asn missense NM_001407664.1:c.5399G>A NP_001394593.1:p.Ser1800Asn missense NM_001407665.1:c.5399G>A NP_001394594.1:p.Ser1800Asn missense NM_001407666.1:c.5399G>A NP_001394595.1:p.Ser1800Asn missense NM_001407667.1:c.5399G>A NP_001394596.1:p.Ser1800Asn missense NM_001407668.1:c.5399G>A NP_001394597.1:p.Ser1800Asn missense NM_001407669.1:c.5399G>A NP_001394598.1:p.Ser1800Asn missense NM_001407670.1:c.5396G>A NP_001394599.1:p.Ser1799Asn missense NM_001407671.1:c.5396G>A NP_001394600.1:p.Ser1799Asn missense NM_001407672.1:c.5396G>A NP_001394601.1:p.Ser1799Asn missense NM_001407673.1:c.5396G>A NP_001394602.1:p.Ser1799Asn missense NM_001407674.1:c.5396G>A NP_001394603.1:p.Ser1799Asn missense NM_001407675.1:c.5396G>A NP_001394604.1:p.Ser1799Asn missense NM_001407676.1:c.5396G>A NP_001394605.1:p.Ser1799Asn missense NM_001407677.1:c.5396G>A NP_001394606.1:p.Ser1799Asn missense NM_001407678.1:c.5396G>A NP_001394607.1:p.Ser1799Asn missense NM_001407679.1:c.5396G>A NP_001394608.1:p.Ser1799Asn missense NM_001407680.1:c.5396G>A NP_001394609.1:p.Ser1799Asn missense NM_001407681.1:c.5393G>A NP_001394610.1:p.Ser1798Asn missense NM_001407682.1:c.5393G>A NP_001394611.1:p.Ser1798Asn missense NM_001407683.1:c.5393G>A NP_001394612.1:p.Ser1798Asn missense NM_001407684.1:c.5393G>A NP_001394613.1:p.Ser1798Asn missense NM_001407685.1:c.5393G>A NP_001394614.1:p.Ser1798Asn missense NM_001407686.1:c.5393G>A NP_001394615.1:p.Ser1798Asn missense NM_001407687.1:c.5393G>A NP_001394616.1:p.Ser1798Asn missense NM_001407688.1:c.5393G>A NP_001394617.1:p.Ser1798Asn missense NM_001407689.1:c.5393G>A NP_001394618.1:p.Ser1798Asn missense NM_001407690.1:c.5390G>A NP_001394619.1:p.Ser1797Asn missense NM_001407691.1:c.5390G>A NP_001394620.1:p.Ser1797Asn missense NM_001407692.1:c.5381G>A NP_001394621.1:p.Ser1794Asn missense NM_001407694.1:c.5381G>A NP_001394623.1:p.Ser1794Asn missense NM_001407695.1:c.5381G>A NP_001394624.1:p.Ser1794Asn missense NM_001407696.1:c.5381G>A NP_001394625.1:p.Ser1794Asn missense NM_001407697.1:c.5381G>A NP_001394626.1:p.Ser1794Asn missense NM_001407698.1:c.5381G>A NP_001394627.1:p.Ser1794Asn missense NM_001407724.1:c.5381G>A NP_001394653.1:p.Ser1794Asn missense NM_001407725.1:c.5381G>A NP_001394654.1:p.Ser1794Asn missense NM_001407726.1:c.5381G>A NP_001394655.1:p.Ser1794Asn missense NM_001407727.1:c.5381G>A NP_001394656.1:p.Ser1794Asn missense NM_001407728.1:c.5381G>A NP_001394657.1:p.Ser1794Asn missense NM_001407729.1:c.5381G>A NP_001394658.1:p.Ser1794Asn missense NM_001407730.1:c.5381G>A NP_001394659.1:p.Ser1794Asn missense NM_001407731.1:c.5381G>A NP_001394660.1:p.Ser1794Asn missense NM_001407732.1:c.5378G>A NP_001394661.1:p.Ser1793Asn missense NM_001407733.1:c.5378G>A NP_001394662.1:p.Ser1793Asn missense NM_001407734.1:c.5378G>A NP_001394663.1:p.Ser1793Asn missense NM_001407735.1:c.5378G>A NP_001394664.1:p.Ser1793Asn missense NM_001407736.1:c.5378G>A NP_001394665.1:p.Ser1793Asn missense NM_001407737.1:c.5378G>A NP_001394666.1:p.Ser1793Asn missense NM_001407738.1:c.5378G>A NP_001394667.1:p.Ser1793Asn missense NM_001407739.1:c.5378G>A NP_001394668.1:p.Ser1793Asn missense NM_001407740.1:c.5378G>A NP_001394669.1:p.Ser1793Asn missense NM_001407741.1:c.5378G>A NP_001394670.1:p.Ser1793Asn missense NM_001407742.1:c.5378G>A NP_001394671.1:p.Ser1793Asn missense NM_001407743.1:c.5378G>A NP_001394672.1:p.Ser1793Asn missense NM_001407744.1:c.5378G>A NP_001394673.1:p.Ser1793Asn missense NM_001407745.1:c.5378G>A NP_001394674.1:p.Ser1793Asn missense NM_001407746.1:c.5378G>A NP_001394675.1:p.Ser1793Asn missense NM_001407747.1:c.5378G>A NP_001394676.1:p.Ser1793Asn missense NM_001407748.1:c.5378G>A NP_001394677.1:p.Ser1793Asn missense NM_001407749.1:c.5378G>A NP_001394678.1:p.Ser1793Asn missense NM_001407750.1:c.5378G>A NP_001394679.1:p.Ser1793Asn missense NM_001407751.1:c.5378G>A NP_001394680.1:p.Ser1793Asn missense NM_001407752.1:c.5378G>A NP_001394681.1:p.Ser1793Asn missense NM_001407838.1:c.5375G>A NP_001394767.1:p.Ser1792Asn missense NM_001407839.1:c.5375G>A NP_001394768.1:p.Ser1792Asn missense NM_001407841.1:c.5375G>A NP_001394770.1:p.Ser1792Asn missense NM_001407842.1:c.5375G>A NP_001394771.1:p.Ser1792Asn missense NM_001407843.1:c.5375G>A NP_001394772.1:p.Ser1792Asn missense NM_001407844.1:c.5375G>A NP_001394773.1:p.Ser1792Asn missense NM_001407845.1:c.5375G>A NP_001394774.1:p.Ser1792Asn missense NM_001407846.1:c.5375G>A NP_001394775.1:p.Ser1792Asn missense NM_001407847.1:c.5375G>A NP_001394776.1:p.Ser1792Asn missense NM_001407848.1:c.5375G>A NP_001394777.1:p.Ser1792Asn missense NM_001407849.1:c.5375G>A NP_001394778.1:p.Ser1792Asn missense NM_001407850.1:c.5375G>A NP_001394779.1:p.Ser1792Asn missense NM_001407851.1:c.5375G>A NP_001394780.1:p.Ser1792Asn missense NM_001407852.1:c.5375G>A NP_001394781.1:p.Ser1792Asn missense NM_001407853.1:c.5375G>A NP_001394782.1:p.Ser1792Asn missense NM_001407854.1:c.*36G>A NM_001407858.1:c.*36G>A NM_001407859.1:c.*36G>A NM_001407860.1:c.*36G>A NM_001407861.1:c.*36G>A NM_001407862.1:c.5321G>A NP_001394791.1:p.Ser1774Asn missense NM_001407863.1:c.5318G>A NP_001394792.1:p.Ser1773Asn missense NM_001407874.1:c.5315G>A NP_001394803.1:p.Ser1772Asn missense NM_001407875.1:c.5315G>A NP_001394804.1:p.Ser1772Asn missense NM_001407879.1:c.5312G>A NP_001394808.1:p.Ser1771Asn missense NM_001407881.1:c.5312G>A NP_001394810.1:p.Ser1771Asn missense NM_001407882.1:c.5312G>A NP_001394811.1:p.Ser1771Asn missense NM_001407884.1:c.5312G>A NP_001394813.1:p.Ser1771Asn missense NM_001407885.1:c.5312G>A NP_001394814.1:p.Ser1771Asn missense NM_001407886.1:c.5312G>A NP_001394815.1:p.Ser1771Asn missense NM_001407887.1:c.5312G>A NP_001394816.1:p.Ser1771Asn missense NM_001407889.1:c.5312G>A NP_001394818.1:p.Ser1771Asn missense NM_001407894.1:c.5309G>A NP_001394823.1:p.Ser1770Asn missense NM_001407895.1:c.5309G>A NP_001394824.1:p.Ser1770Asn missense NM_001407896.1:c.5309G>A NP_001394825.1:p.Ser1770Asn missense NM_001407897.1:c.5309G>A NP_001394826.1:p.Ser1770Asn missense NM_001407898.1:c.5309G>A NP_001394827.1:p.Ser1770Asn missense NM_001407899.1:c.5309G>A NP_001394828.1:p.Ser1770Asn missense NM_001407900.1:c.5309G>A NP_001394829.1:p.Ser1770Asn missense NM_001407902.1:c.5309G>A NP_001394831.1:p.Ser1770Asn missense NM_001407904.1:c.5309G>A NP_001394833.1:p.Ser1770Asn missense NM_001407906.1:c.5309G>A NP_001394835.1:p.Ser1770Asn missense NM_001407907.1:c.5309G>A NP_001394836.1:p.Ser1770Asn missense NM_001407908.1:c.5309G>A NP_001394837.1:p.Ser1770Asn missense NM_001407909.1:c.5309G>A NP_001394838.1:p.Ser1770Asn missense NM_001407910.1:c.5309G>A NP_001394839.1:p.Ser1770Asn missense NM_001407915.1:c.5306G>A NP_001394844.1:p.Ser1769Asn missense NM_001407916.1:c.5306G>A NP_001394845.1:p.Ser1769Asn missense NM_001407917.1:c.5306G>A NP_001394846.1:p.Ser1769Asn missense NM_001407918.1:c.5306G>A NP_001394847.1:p.Ser1769Asn missense NM_001407919.1:c.5270G>A NP_001394848.1:p.Ser1757Asn missense NM_001407920.1:c.5258G>A NP_001394849.1:p.Ser1753Asn missense NM_001407921.1:c.5258G>A NP_001394850.1:p.Ser1753Asn missense NM_001407922.1:c.5258G>A NP_001394851.1:p.Ser1753Asn missense NM_001407923.1:c.5258G>A NP_001394852.1:p.Ser1753Asn missense NM_001407924.1:c.5258G>A NP_001394853.1:p.Ser1753Asn missense NM_001407925.1:c.5258G>A NP_001394854.1:p.Ser1753Asn missense NM_001407926.1:c.5258G>A NP_001394855.1:p.Ser1753Asn missense NM_001407927.1:c.5255G>A NP_001394856.1:p.Ser1752Asn missense NM_001407928.1:c.5255G>A NP_001394857.1:p.Ser1752Asn missense NM_001407929.1:c.5255G>A NP_001394858.1:p.Ser1752Asn missense NM_001407930.1:c.5255G>A NP_001394859.1:p.Ser1752Asn missense NM_001407931.1:c.5255G>A NP_001394860.1:p.Ser1752Asn missense NM_001407932.1:c.5255G>A NP_001394861.1:p.Ser1752Asn missense NM_001407933.1:c.5255G>A NP_001394862.1:p.Ser1752Asn missense NM_001407934.1:c.5252G>A NP_001394863.1:p.Ser1751Asn missense NM_001407935.1:c.5252G>A NP_001394864.1:p.Ser1751Asn missense NM_001407936.1:c.5252G>A NP_001394865.1:p.Ser1751Asn missense NM_001407937.1:c.*36G>A NM_001407938.1:c.*36G>A NM_001407939.1:c.*36G>A NM_001407940.1:c.*36G>A NM_001407941.1:c.*36G>A NM_001407942.1:c.*36G>A NM_001407943.1:c.*36G>A NM_001407944.1:c.*36G>A NM_001407945.1:c.*36G>A NM_001407946.1:c.5189G>A NP_001394875.1:p.Ser1730Asn missense NM_001407947.1:c.5189G>A NP_001394876.1:p.Ser1730Asn missense NM_001407948.1:c.5189G>A NP_001394877.1:p.Ser1730Asn missense NM_001407949.1:c.5189G>A NP_001394878.1:p.Ser1730Asn missense NM_001407950.1:c.5186G>A NP_001394879.1:p.Ser1729Asn missense NM_001407951.1:c.5186G>A NP_001394880.1:p.Ser1729Asn missense NM_001407952.1:c.5186G>A NP_001394881.1:p.Ser1729Asn missense NM_001407953.1:c.5186G>A NP_001394882.1:p.Ser1729Asn missense NM_001407954.1:c.5186G>A NP_001394883.1:p.Ser1729Asn missense NM_001407955.1:c.5186G>A NP_001394884.1:p.Ser1729Asn missense NM_001407956.1:c.5183G>A NP_001394885.1:p.Ser1728Asn missense NM_001407957.1:c.5183G>A NP_001394886.1:p.Ser1728Asn missense NM_001407958.1:c.5183G>A NP_001394887.1:p.Ser1728Asn missense NM_001407959.1:c.5141G>A NP_001394888.1:p.Ser1714Asn missense NM_001407960.1:c.5138G>A NP_001394889.1:p.Ser1713Asn missense NM_001407962.1:c.5138G>A NP_001394891.1:p.Ser1713Asn missense NM_001407963.1:c.5135G>A NP_001394892.1:p.Ser1712Asn missense NM_001407964.1:c.5060G>A NP_001394893.1:p.Ser1687Asn missense NM_001407965.1:c.5015G>A NP_001394894.1:p.Ser1672Asn missense NM_001407966.1:c.4634G>A NP_001394895.1:p.Ser1545Asn missense NM_001407967.1:c.4631G>A NP_001394896.1:p.Ser1544Asn missense NM_001407968.1:c.2918G>A NP_001394897.1:p.Ser973Asn missense NM_001407969.1:c.2915G>A NP_001394898.1:p.Ser972Asn missense NM_001407970.1:c.2279G>A NP_001394899.1:p.Ser760Asn missense NM_001407971.1:c.2279G>A NP_001394900.1:p.Ser760Asn missense NM_001407972.1:c.2276G>A NP_001394901.1:p.Ser759Asn missense NM_001407973.1:c.2213G>A NP_001394902.1:p.Ser738Asn missense NM_001407974.1:c.2213G>A NP_001394903.1:p.Ser738Asn missense NM_001407975.1:c.2213G>A NP_001394904.1:p.Ser738Asn missense NM_001407976.1:c.2213G>A NP_001394905.1:p.Ser738Asn missense NM_001407977.1:c.2213G>A NP_001394906.1:p.Ser738Asn missense NM_001407978.1:c.2213G>A NP_001394907.1:p.Ser738Asn missense NM_001407979.1:c.2210G>A NP_001394908.1:p.Ser737Asn missense NM_001407980.1:c.2210G>A NP_001394909.1:p.Ser737Asn missense NM_001407981.1:c.2210G>A NP_001394910.1:p.Ser737Asn missense NM_001407982.1:c.2210G>A NP_001394911.1:p.Ser737Asn missense NM_001407983.1:c.2210G>A NP_001394912.1:p.Ser737Asn missense NM_001407984.1:c.2210G>A NP_001394913.1:p.Ser737Asn missense NM_001407985.1:c.2210G>A NP_001394914.1:p.Ser737Asn missense NM_001407986.1:c.2210G>A NP_001394915.1:p.Ser737Asn missense NM_001407990.1:c.2210G>A NP_001394919.1:p.Ser737Asn missense NM_001407991.1:c.2210G>A NP_001394920.1:p.Ser737Asn missense NM_001407992.1:c.2210G>A NP_001394921.1:p.Ser737Asn missense NM_001407993.1:c.2210G>A NP_001394922.1:p.Ser737Asn missense NM_001408392.1:c.2207G>A NP_001395321.1:p.Ser736Asn missense NM_001408396.1:c.2207G>A NP_001395325.1:p.Ser736Asn missense NM_001408397.1:c.2207G>A NP_001395326.1:p.Ser736Asn missense NM_001408398.1:c.2207G>A NP_001395327.1:p.Ser736Asn missense NM_001408399.1:c.2207G>A NP_001395328.1:p.Ser736Asn missense NM_001408400.1:c.2207G>A NP_001395329.1:p.Ser736Asn missense NM_001408401.1:c.2207G>A NP_001395330.1:p.Ser736Asn missense NM_001408402.1:c.2207G>A NP_001395331.1:p.Ser736Asn missense NM_001408403.1:c.2207G>A NP_001395332.1:p.Ser736Asn missense NM_001408404.1:c.2207G>A NP_001395333.1:p.Ser736Asn missense NM_001408406.1:c.2204G>A NP_001395335.1:p.Ser735Asn missense NM_001408407.1:c.2204G>A NP_001395336.1:p.Ser735Asn missense NM_001408408.1:c.2204G>A NP_001395337.1:p.Ser735Asn missense NM_001408409.1:c.2201G>A NP_001395338.1:p.Ser734Asn missense NM_001408410.1:c.2138G>A NP_001395339.1:p.Ser713Asn missense NM_001408411.1:c.2135G>A NP_001395340.1:p.Ser712Asn missense NM_001408412.1:c.2132G>A NP_001395341.1:p.Ser711Asn missense NM_001408413.1:c.2132G>A NP_001395342.1:p.Ser711Asn missense NM_001408414.1:c.2132G>A NP_001395343.1:p.Ser711Asn missense NM_001408415.1:c.2132G>A NP_001395344.1:p.Ser711Asn missense NM_001408416.1:c.2132G>A NP_001395345.1:p.Ser711Asn missense NM_001408418.1:c.2096G>A NP_001395347.1:p.Ser699Asn missense NM_001408419.1:c.2096G>A NP_001395348.1:p.Ser699Asn missense NM_001408420.1:c.2096G>A NP_001395349.1:p.Ser699Asn missense NM_001408421.1:c.2093G>A NP_001395350.1:p.Ser698Asn missense NM_001408422.1:c.2093G>A NP_001395351.1:p.Ser698Asn missense NM_001408423.1:c.2093G>A NP_001395352.1:p.Ser698Asn missense NM_001408424.1:c.2093G>A NP_001395353.1:p.Ser698Asn missense NM_001408425.1:c.2090G>A NP_001395354.1:p.Ser697Asn missense NM_001408426.1:c.2090G>A NP_001395355.1:p.Ser697Asn missense NM_001408427.1:c.2090G>A NP_001395356.1:p.Ser697Asn missense NM_001408428.1:c.2090G>A NP_001395357.1:p.Ser697Asn missense NM_001408429.1:c.2090G>A NP_001395358.1:p.Ser697Asn missense NM_001408430.1:c.2090G>A NP_001395359.1:p.Ser697Asn missense NM_001408431.1:c.2090G>A NP_001395360.1:p.Ser697Asn missense NM_001408432.1:c.2087G>A NP_001395361.1:p.Ser696Asn missense NM_001408433.1:c.2087G>A NP_001395362.1:p.Ser696Asn missense NM_001408434.1:c.2087G>A NP_001395363.1:p.Ser696Asn missense NM_001408435.1:c.2087G>A NP_001395364.1:p.Ser696Asn missense NM_001408436.1:c.2087G>A NP_001395365.1:p.Ser696Asn missense NM_001408437.1:c.2087G>A NP_001395366.1:p.Ser696Asn missense NM_001408438.1:c.2087G>A NP_001395367.1:p.Ser696Asn missense NM_001408439.1:c.2087G>A NP_001395368.1:p.Ser696Asn missense NM_001408440.1:c.2087G>A NP_001395369.1:p.Ser696Asn missense NM_001408441.1:c.2087G>A NP_001395370.1:p.Ser696Asn missense NM_001408442.1:c.2087G>A NP_001395371.1:p.Ser696Asn missense NM_001408443.1:c.2087G>A NP_001395372.1:p.Ser696Asn missense NM_001408444.1:c.2087G>A NP_001395373.1:p.Ser696Asn missense NM_001408445.1:c.2084G>A NP_001395374.1:p.Ser695Asn missense NM_001408446.1:c.2084G>A NP_001395375.1:p.Ser695Asn missense NM_001408447.1:c.2084G>A NP_001395376.1:p.Ser695Asn missense NM_001408448.1:c.2084G>A NP_001395377.1:p.Ser695Asn missense NM_001408450.1:c.2084G>A NP_001395379.1:p.Ser695Asn missense NM_001408451.1:c.2078G>A NP_001395380.1:p.Ser693Asn missense NM_001408452.1:c.2072G>A NP_001395381.1:p.Ser691Asn missense NM_001408453.1:c.2072G>A NP_001395382.1:p.Ser691Asn missense NM_001408454.1:c.2072G>A NP_001395383.1:p.Ser691Asn missense NM_001408455.1:c.2072G>A NP_001395384.1:p.Ser691Asn missense NM_001408456.1:c.2072G>A NP_001395385.1:p.Ser691Asn missense NM_001408457.1:c.2072G>A NP_001395386.1:p.Ser691Asn missense NM_001408458.1:c.2069G>A NP_001395387.1:p.Ser690Asn missense NM_001408459.1:c.2069G>A NP_001395388.1:p.Ser690Asn missense NM_001408460.1:c.2069G>A NP_001395389.1:p.Ser690Asn missense NM_001408461.1:c.2069G>A NP_001395390.1:p.Ser690Asn missense NM_001408462.1:c.2069G>A NP_001395391.1:p.Ser690Asn missense NM_001408463.1:c.2069G>A NP_001395392.1:p.Ser690Asn missense NM_001408464.1:c.2069G>A NP_001395393.1:p.Ser690Asn missense NM_001408465.1:c.2069G>A NP_001395394.1:p.Ser690Asn missense NM_001408466.1:c.2069G>A NP_001395395.1:p.Ser690Asn missense NM_001408467.1:c.2069G>A NP_001395396.1:p.Ser690Asn missense NM_001408468.1:c.2066G>A NP_001395397.1:p.Ser689Asn missense NM_001408469.1:c.2066G>A NP_001395398.1:p.Ser689Asn missense NM_001408470.1:c.2066G>A NP_001395399.1:p.Ser689Asn missense NM_001408472.1:c.*36G>A NM_001408473.1:c.*36G>A NM_001408474.1:c.2012G>A NP_001395403.1:p.Ser671Asn missense NM_001408475.1:c.2009G>A NP_001395404.1:p.Ser670Asn missense NM_001408476.1:c.2009G>A NP_001395405.1:p.Ser670Asn missense NM_001408478.1:c.2003G>A NP_001395407.1:p.Ser668Asn missense NM_001408479.1:c.2003G>A NP_001395408.1:p.Ser668Asn missense NM_001408480.1:c.2003G>A NP_001395409.1:p.Ser668Asn missense NM_001408481.1:c.2000G>A NP_001395410.1:p.Ser667Asn missense NM_001408482.1:c.2000G>A NP_001395411.1:p.Ser667Asn missense NM_001408483.1:c.2000G>A NP_001395412.1:p.Ser667Asn missense NM_001408484.1:c.2000G>A NP_001395413.1:p.Ser667Asn missense NM_001408485.1:c.2000G>A NP_001395414.1:p.Ser667Asn missense NM_001408489.1:c.2000G>A NP_001395418.1:p.Ser667Asn missense NM_001408490.1:c.2000G>A NP_001395419.1:p.Ser667Asn missense NM_001408491.1:c.2000G>A NP_001395420.1:p.Ser667Asn missense NM_001408492.1:c.1997G>A NP_001395421.1:p.Ser666Asn missense NM_001408493.1:c.1997G>A NP_001395422.1:p.Ser666Asn missense NM_001408494.1:c.1973G>A NP_001395423.1:p.Ser658Asn missense NM_001408495.1:c.1967G>A NP_001395424.1:p.Ser656Asn missense NM_001408496.1:c.1949G>A NP_001395425.1:p.Ser650Asn missense NM_001408497.1:c.1949G>A NP_001395426.1:p.Ser650Asn missense NM_001408498.1:c.1949G>A NP_001395427.1:p.Ser650Asn missense NM_001408499.1:c.1949G>A NP_001395428.1:p.Ser650Asn missense NM_001408500.1:c.1949G>A NP_001395429.1:p.Ser650Asn missense NM_001408501.1:c.1949G>A NP_001395430.1:p.Ser650Asn missense NM_001408502.1:c.1946G>A NP_001395431.1:p.Ser649Asn missense NM_001408503.1:c.1946G>A NP_001395432.1:p.Ser649Asn missense NM_001408504.1:c.1946G>A NP_001395433.1:p.Ser649Asn missense NM_001408505.1:c.1943G>A NP_001395434.1:p.Ser648Asn missense NM_001408506.1:c.1886G>A NP_001395435.1:p.Ser629Asn missense NM_001408507.1:c.1883G>A NP_001395436.1:p.Ser628Asn missense NM_001408508.1:c.1874G>A NP_001395437.1:p.Ser625Asn missense NM_001408509.1:c.1871G>A NP_001395438.1:p.Ser624Asn missense NM_001408510.1:c.1832G>A NP_001395439.1:p.Ser611Asn missense NM_001408511.1:c.1829G>A NP_001395440.1:p.Ser610Asn missense NM_001408512.1:c.1709G>A NP_001395441.1:p.Ser570Asn missense NM_001408513.1:c.1682G>A NP_001395442.1:p.Ser561Asn missense NM_001408514.1:c.1286G>A NP_001395443.1:p.Ser429Asn missense NM_007297.4:c.5381G>A NP_009228.2:p.Ser1794Asn missense NM_007298.4:c.2210G>A NP_009229.2:p.Ser737Asn missense NM_007299.4:c.*36G>A 3 prime UTR NM_007300.4:c.5585G>A NP_009231.2:p.Ser1862Asn missense NM_007304.2:c.2210G>A NP_009235.2:p.Ser737Asn missense NR_027676.2:n.5699G>A non-coding transcript variant NC_000017.11:g.43045748C>T NC_000017.10:g.41197765C>T NG_005905.2:g.172236G>A LRG_292:g.172236G>A LRG_292t1:c.5522G>A LRG_292p1:p.Ser1841Asn U14680.1:n.5641G>A - Protein change
- S1841N, S1862N, S737N, S1794N, S1714N, S1751N, S1757N, S1772N, S1773N, S1774N, S1792N, S1797N, S1798N, S1813N, S1821N, S1839N, S1861N, S611N, S625N, S628N, S629N, S650N, S668N, S689N, S759N, S1712N, S735N, S738N, S1799N, S1836N, S570N, S610N, S624N, S648N, S656N, S667N, S697N, S711N, S973N, S1544N, S1672N, S1730N, S1753N, S1769N, S1771N, S1800N, S1815N, S1822N, S1838N, S1863N, S429N, S561N, S658N, S671N, S690N, S691N, S698N, S734N, S736N, S760N, S972N, S1545N, S1687N, S1713N, S1728N, S1729N, S1752N, S1770N, S1793N, S1814N, S1837N, S1840N, S649N, S666N, S670N, S693N, S695N, S696N, S699N, S712N, S713N
- Other names
- -
- Canonical SPDI
- NC_000017.11:43045747:C:T
-
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.5522G>A, a MISSENSE variant, produced a function score of -2.26, 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. |
|---|---|---|---|---|
| Uncertain significance (2) |
no assertion criteria provided
|
Jun 12, 2000 | RCV000112694.12 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Aug 25, 2023 | RCV000236784.11 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Apr 5, 2023 | RCV000583863.17 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Oct 19, 2020 | RCV001254337.18 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV002250546.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Breast Center, Key Laboratory of Carcinogenesis and Translational Research
Accession: SCV001430322.1
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Chinese
|
|
|
Uncertain significance
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001536377.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30765603, 28781887, 30209399, 16786532, 20378548, 16969499, 17005433, 25748678, 30257991). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822). ClinVar contains an entry for this variant (Variation ID: 55613). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1841 of the BRCA1 protein (p.Ser1841Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. (less)
|
|
|
Uncertain significance
(Aug 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000688640.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with asparagine at codon 1841 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces serine with asparagine at codon 1841 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant reduces homology-directed DNA repair activity and has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 25748678, 30209399, 30257991). This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 28364669, 29752822). A multifactorial analysis has reported segregation, co-occurrence, tumor pathology, and family history likelihood ratios for pathogenicity of 14.79, 1.067, 0.089 and 5.97, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Apr 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002653674.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide … (more)
The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5522. The serine at codon 1841 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in patient cohorts with breast and ovarian cancer (Ryu JM et al. Breast, 2017 Jun;33:109-116; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has been shown to have a detrimental effect on protein stability, structure, and binding in functional assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69), and was determined to be deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, p.S1841N is highly disruptive to this region of BRCA1 (Ambry internal data; Gaiser OJ et al. Biochemistry. 2004 Dec;43(51):15983-95). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Uncertain significance
(Nov 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001133640.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 03, 2022 |
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Likely pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292708.11
First in ClinVar: Jul 24, 2016 Last updated: Aug 31, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5641G>A; This variant is associated with the following publications: (PMID: 20608970, 17305420, 15235020, 15172985, 16969499, 20378548, 17005433, 10946236, 20516115, 31131967, 25748678, 28781887, 28364669, 30765603, 16786532, 30257991, 25348405, 32377563, 30209399, 32803532, 29884841, 35665744, 35918668, 29752822) (less)
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Uncertain significance
(Jun 12, 2000)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145566.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Geographic origin: Central/Eastern European
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: France
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Center for Precision Medicine, Meizhou People's Hospital
Accession: SCV002520856.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
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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: SCV001244053.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-2.26214444108425
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Comment:
Comment:
This missense variant replaces serine with asparagine at codon 1841 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant reduces homology-directed DNA repair activity and has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 25748678, 30209399, 30257991). This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 28364669, 29752822). A multifactorial analysis has reported segregation, co-occurrence, tumor pathology, and family history likelihood ratios for pathogenicity of 14.79, 1.067, 0.089 and 5.97, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5522. The serine at codon 1841 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in patient cohorts with breast and ovarian cancer (Ryu JM et al. Breast, 2017 Jun;33:109-116; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has been shown to have a detrimental effect on protein stability, structure, and binding in functional assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69), and was determined to be deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, p.S1841N is highly disruptive to this region of BRCA1 (Ambry internal data; Gaiser OJ et al. Biochemistry. 2004 Dec;43(51):15983-95). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5641G>A; This variant is associated with the following publications: (PMID: 20608970, 17305420, 15235020, 15172985, 16969499, 20378548, 17005433, 10946236, 20516115, 31131967, 25748678, 28781887, 28364669, 30765603, 16786532, 30257991, 25348405, 32377563, 30209399, 32803532, 29884841, 35665744, 35918668, 29752822)
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: SCV001244053.1
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Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5522G>A, a MISSENSE variant, produced a function score of -2.26, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.5522G>A, a MISSENSE variant, produced a function score of -2.26, 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:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30765603, 28781887, 30209399, 16786532, 20378548, 16969499, 17005433, 25748678, 30257991). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822). ClinVar contains an entry for this variant (Variation ID: 55613). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 1841 of the BRCA1 protein (p.Ser1841Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine.
Comment:
This missense variant replaces serine with asparagine at codon 1841 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant reduces homology-directed DNA repair activity and has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 25748678, 30209399, 30257991). This variant has been reported in two individuals affected with breast or ovarian cancer (PMID: 28364669, 29752822). A multifactorial analysis has reported segregation, co-occurrence, tumor pathology, and family history likelihood ratios for pathogenicity of 14.79, 1.067, 0.089 and 5.97, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.S1841N variant (also known as c.5522G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5522. The serine at codon 1841 is replaced by asparagine, an amino acid with highly similar properties. This variant has been identified in patient cohorts with breast and ovarian cancer (Ryu JM et al. Breast, 2017 Jun;33:109-116; Li JY et al. Int. J. Cancer, 2019 01;144:281-289). This alteration has been shown to have a detrimental effect on protein stability, structure, and binding in functional assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol. Cancer Res., 2019 01;17:54-69), and was determined to be deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, p.S1841N is highly disruptive to this region of BRCA1 (Ambry internal data; Gaiser OJ et al. Biochemistry. 2004 Dec;43(51):15983-95). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5641G>A; This variant is associated with the following publications: (PMID: 20608970, 17305420, 15235020, 15172985, 16969499, 20378548, 17005433, 10946236, 20516115, 31131967, 25748678, 28781887, 28364669, 30765603, 16786532, 30257991, 25348405, 32377563, 30209399, 32803532, 29884841, 35665744, 35918668, 29752822)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. | Parsons MT | Human mutation | 2019 | PMID: 31131967 |
| Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation. | Fernandes VC | The Journal of biological chemistry | 2019 | PMID: 30765603 |
| Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk. | Petitalot A | Molecular cancer research : MCR | 2019 | PMID: 30257991 |
| Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Suggestion of BRCA1 c.5339T>C (p.L1780P) variant confer from 'unknown significance' to 'Likely pathogenic' based on clinical evidence in Korea. | Ryu JM | Breast (Edinburgh, Scotland) | 2017 | PMID: 28364669 |
| Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance. | Woods NT | NPJ genomic medicine | 2016 | PMID: 28781887 |
| Protein stability versus function: effects of destabilizing missense mutations on BRCA1 DNA repair activity. | Gaboriau DC | The Biochemical journal | 2015 | PMID: 25748678 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| Toward classification of BRCA1 missense variants using a biophysical approach. | Rowling PJ | The Journal of biological chemistry | 2010 | PMID: 20378548 |
| Functional impact of missense variants in BRCA1 predicted by supervised learning. | Karchin R | PLoS computational biology | 2007 | PMID: 17305420 |
| Specific changes in the proteomic pattern produced by the BRCA1-Ser1841Asn missense mutation. | Crugliano T | The international journal of biochemistry & cell biology | 2007 | PMID: 17005433 |
| Missense mutations of BRCA1 gene affect the binding with p53 both in vitro and in vivo. | Quaresima B | Oncology reports | 2006 | PMID: 16969499 |
| In vitro analysis of genomic instability triggered by BRCA1 missense mutations. | Quaresima B | Human mutation | 2006 | PMID: 16786532 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
| Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. | Mirkovic N | Cancer research | 2004 | PMID: 15172985 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80357368 ...
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at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.