Data included in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 0.04 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on SIFT, Align GVGD and Polyphen HumVar (PP3). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018), an assay well validated against ENIGMA/ClinVar (PS3) The variant is located in the BRCT1 domain (PM1_sup). c.4963T>C p.(Ser1655Pro) previously classified as pathogenic by CanVIG (July 2018) (PM5). Data not included in classification: Extensive additional functional data demonstrating variant to be deleterious: Williams et al. Carvalho et al. Lee et al., Bouwman et al (2013), Domchek et al (2013), Shakya (2011). Anantha et al (2017) elife; 6 e21350 Apr: undertook functional studies confirming reduced HR activity. Computer based algorithms predicting variant to be deleterious: Iverson (2012), Gomez-Garcia (2009) and Karchin (2007). Segregation 1 in 4 in UK family. Gomez-Garcia et al (2009) demonstrated segregation in 6/6 individuals (across 2 families) but no further details provided. There are additional reports of this variant in ClinVar (2), BIC (3) and BRCA1 LOVD (11).
ClinVar Genomic variation as it relates to human health
NM_007294.4(BRCA1):c.4964C>T (p.Ser1655Phe)
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.
(13)
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.
Pathogenic/Likely pathogenic
13
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.4964C>T (p.Ser1655Phe)
Variation ID: 55333 Accession: VCV000055333.65
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 43070950 (GRCh38) [ NCBI UCSC ] 17: 41222967 (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 Jun 2, 2024 May 27, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007294.4:c.4964C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009225.1:p.Ser1655Phe missense NM_001407571.1:c.4751C>T NP_001394500.1:p.Ser1584Phe missense NM_001407581.1:c.5030C>T NP_001394510.1:p.Ser1677Phe missense NM_001407582.1:c.5030C>T NP_001394511.1:p.Ser1677Phe missense NM_001407583.1:c.5027C>T NP_001394512.1:p.Ser1676Phe missense NM_001407585.1:c.5027C>T NP_001394514.1:p.Ser1676Phe missense NM_001407587.1:c.5027C>T NP_001394516.1:p.Ser1676Phe missense NM_001407590.1:c.5024C>T NP_001394519.1:p.Ser1675Phe missense NM_001407591.1:c.5024C>T NP_001394520.1:p.Ser1675Phe missense NM_001407593.1:c.4964C>T NP_001394522.1:p.Ser1655Phe missense NM_001407594.1:c.4964C>T NP_001394523.1:p.Ser1655Phe missense NM_001407596.1:c.4964C>T NP_001394525.1:p.Ser1655Phe missense NM_001407597.1:c.4964C>T NP_001394526.1:p.Ser1655Phe missense NM_001407598.1:c.4964C>T NP_001394527.1:p.Ser1655Phe missense NM_001407602.1:c.4964C>T NP_001394531.1:p.Ser1655Phe missense NM_001407603.1:c.4964C>T NP_001394532.1:p.Ser1655Phe missense NM_001407605.1:c.4964C>T NP_001394534.1:p.Ser1655Phe missense NM_001407610.1:c.4961C>T NP_001394539.1:p.Ser1654Phe missense NM_001407611.1:c.4961C>T NP_001394540.1:p.Ser1654Phe missense NM_001407612.1:c.4961C>T NP_001394541.1:p.Ser1654Phe missense NM_001407613.1:c.4961C>T NP_001394542.1:p.Ser1654Phe missense NM_001407614.1:c.4961C>T NP_001394543.1:p.Ser1654Phe missense NM_001407615.1:c.4961C>T NP_001394544.1:p.Ser1654Phe missense NM_001407616.1:c.4961C>T NP_001394545.1:p.Ser1654Phe missense NM_001407617.1:c.4961C>T NP_001394546.1:p.Ser1654Phe missense NM_001407618.1:c.4961C>T NP_001394547.1:p.Ser1654Phe missense NM_001407619.1:c.4961C>T NP_001394548.1:p.Ser1654Phe missense NM_001407620.1:c.4961C>T NP_001394549.1:p.Ser1654Phe missense NM_001407621.1:c.4961C>T NP_001394550.1:p.Ser1654Phe missense NM_001407622.1:c.4961C>T NP_001394551.1:p.Ser1654Phe missense NM_001407623.1:c.4961C>T NP_001394552.1:p.Ser1654Phe missense NM_001407624.1:c.4961C>T NP_001394553.1:p.Ser1654Phe missense NM_001407625.1:c.4961C>T NP_001394554.1:p.Ser1654Phe missense NM_001407626.1:c.4961C>T NP_001394555.1:p.Ser1654Phe missense NM_001407627.1:c.4958C>T NP_001394556.1:p.Ser1653Phe missense NM_001407628.1:c.4958C>T NP_001394557.1:p.Ser1653Phe missense NM_001407629.1:c.4958C>T NP_001394558.1:p.Ser1653Phe missense NM_001407630.1:c.4958C>T NP_001394559.1:p.Ser1653Phe missense NM_001407631.1:c.4958C>T NP_001394560.1:p.Ser1653Phe missense NM_001407632.1:c.4958C>T NP_001394561.1:p.Ser1653Phe missense NM_001407633.1:c.4958C>T NP_001394562.1:p.Ser1653Phe missense NM_001407634.1:c.4958C>T NP_001394563.1:p.Ser1653Phe missense NM_001407635.1:c.4958C>T NP_001394564.1:p.Ser1653Phe missense NM_001407636.1:c.4958C>T NP_001394565.1:p.Ser1653Phe missense NM_001407637.1:c.4958C>T NP_001394566.1:p.Ser1653Phe missense NM_001407638.1:c.4958C>T NP_001394567.1:p.Ser1653Phe missense NM_001407639.1:c.4958C>T NP_001394568.1:p.Ser1653Phe missense NM_001407640.1:c.4958C>T NP_001394569.1:p.Ser1653Phe missense NM_001407641.1:c.4958C>T NP_001394570.1:p.Ser1653Phe missense NM_001407642.1:c.4958C>T NP_001394571.1:p.Ser1653Phe missense NM_001407644.1:c.4955C>T NP_001394573.1:p.Ser1652Phe missense NM_001407645.1:c.4955C>T NP_001394574.1:p.Ser1652Phe missense NM_001407646.1:c.4952C>T NP_001394575.1:p.Ser1651Phe missense NM_001407647.1:c.4949C>T NP_001394576.1:p.Ser1650Phe missense NM_001407648.1:c.4907C>T NP_001394577.1:p.Ser1636Phe missense NM_001407649.1:c.4904C>T NP_001394578.1:p.Ser1635Phe missense NM_001407652.1:c.4964C>T NP_001394581.1:p.Ser1655Phe missense NM_001407653.1:c.4886C>T NP_001394582.1:p.Ser1629Phe missense NM_001407654.1:c.4886C>T NP_001394583.1:p.Ser1629Phe missense NM_001407655.1:c.4886C>T NP_001394584.1:p.Ser1629Phe missense NM_001407656.1:c.4883C>T NP_001394585.1:p.Ser1628Phe missense NM_001407657.1:c.4883C>T NP_001394586.1:p.Ser1628Phe missense NM_001407658.1:c.4883C>T NP_001394587.1:p.Ser1628Phe missense NM_001407659.1:c.4880C>T NP_001394588.1:p.Ser1627Phe missense NM_001407660.1:c.4880C>T NP_001394589.1:p.Ser1627Phe missense NM_001407661.1:c.4880C>T NP_001394590.1:p.Ser1627Phe missense NM_001407662.1:c.4880C>T NP_001394591.1:p.Ser1627Phe missense NM_001407663.1:c.4880C>T NP_001394592.1:p.Ser1627Phe missense NM_001407664.1:c.4841C>T NP_001394593.1:p.Ser1614Phe missense NM_001407665.1:c.4841C>T NP_001394594.1:p.Ser1614Phe missense NM_001407666.1:c.4841C>T NP_001394595.1:p.Ser1614Phe missense NM_001407667.1:c.4841C>T NP_001394596.1:p.Ser1614Phe missense NM_001407668.1:c.4841C>T NP_001394597.1:p.Ser1614Phe missense NM_001407669.1:c.4841C>T NP_001394598.1:p.Ser1614Phe missense NM_001407670.1:c.4838C>T NP_001394599.1:p.Ser1613Phe missense NM_001407671.1:c.4838C>T NP_001394600.1:p.Ser1613Phe missense NM_001407672.1:c.4838C>T NP_001394601.1:p.Ser1613Phe missense NM_001407673.1:c.4838C>T NP_001394602.1:p.Ser1613Phe missense NM_001407674.1:c.4838C>T NP_001394603.1:p.Ser1613Phe missense NM_001407675.1:c.4838C>T NP_001394604.1:p.Ser1613Phe missense NM_001407676.1:c.4838C>T NP_001394605.1:p.Ser1613Phe missense NM_001407677.1:c.4838C>T NP_001394606.1:p.Ser1613Phe missense NM_001407678.1:c.4838C>T NP_001394607.1:p.Ser1613Phe missense NM_001407679.1:c.4838C>T NP_001394608.1:p.Ser1613Phe missense NM_001407680.1:c.4838C>T NP_001394609.1:p.Ser1613Phe missense NM_001407681.1:c.4835C>T NP_001394610.1:p.Ser1612Phe missense NM_001407682.1:c.4835C>T NP_001394611.1:p.Ser1612Phe missense NM_001407683.1:c.4835C>T NP_001394612.1:p.Ser1612Phe missense NM_001407684.1:c.4964C>T NP_001394613.1:p.Ser1655Phe missense NM_001407685.1:c.4835C>T NP_001394614.1:p.Ser1612Phe missense NM_001407686.1:c.4835C>T NP_001394615.1:p.Ser1612Phe missense NM_001407687.1:c.4835C>T NP_001394616.1:p.Ser1612Phe missense NM_001407688.1:c.4835C>T NP_001394617.1:p.Ser1612Phe missense NM_001407689.1:c.4835C>T NP_001394618.1:p.Ser1612Phe missense NM_001407690.1:c.4832C>T NP_001394619.1:p.Ser1611Phe missense NM_001407691.1:c.4832C>T NP_001394620.1:p.Ser1611Phe missense NM_001407692.1:c.4823C>T NP_001394621.1:p.Ser1608Phe missense NM_001407694.1:c.4823C>T NP_001394623.1:p.Ser1608Phe missense NM_001407695.1:c.4823C>T NP_001394624.1:p.Ser1608Phe missense NM_001407696.1:c.4823C>T NP_001394625.1:p.Ser1608Phe missense NM_001407697.1:c.4823C>T NP_001394626.1:p.Ser1608Phe missense NM_001407698.1:c.4823C>T NP_001394627.1:p.Ser1608Phe missense NM_001407724.1:c.4823C>T NP_001394653.1:p.Ser1608Phe missense NM_001407725.1:c.4823C>T NP_001394654.1:p.Ser1608Phe missense NM_001407726.1:c.4823C>T NP_001394655.1:p.Ser1608Phe missense NM_001407727.1:c.4823C>T NP_001394656.1:p.Ser1608Phe missense NM_001407728.1:c.4823C>T NP_001394657.1:p.Ser1608Phe missense NM_001407729.1:c.4823C>T NP_001394658.1:p.Ser1608Phe missense NM_001407730.1:c.4823C>T NP_001394659.1:p.Ser1608Phe missense NM_001407731.1:c.4823C>T NP_001394660.1:p.Ser1608Phe missense NM_001407732.1:c.4820C>T NP_001394661.1:p.Ser1607Phe missense NM_001407733.1:c.4820C>T NP_001394662.1:p.Ser1607Phe missense NM_001407734.1:c.4820C>T NP_001394663.1:p.Ser1607Phe missense NM_001407735.1:c.4820C>T NP_001394664.1:p.Ser1607Phe missense NM_001407736.1:c.4820C>T NP_001394665.1:p.Ser1607Phe missense NM_001407737.1:c.4820C>T NP_001394666.1:p.Ser1607Phe missense NM_001407738.1:c.4820C>T NP_001394667.1:p.Ser1607Phe missense NM_001407739.1:c.4820C>T NP_001394668.1:p.Ser1607Phe missense NM_001407740.1:c.4820C>T NP_001394669.1:p.Ser1607Phe missense NM_001407741.1:c.4820C>T NP_001394670.1:p.Ser1607Phe missense NM_001407742.1:c.4820C>T NP_001394671.1:p.Ser1607Phe missense NM_001407743.1:c.4820C>T NP_001394672.1:p.Ser1607Phe missense NM_001407744.1:c.4820C>T NP_001394673.1:p.Ser1607Phe missense NM_001407745.1:c.4820C>T NP_001394674.1:p.Ser1607Phe missense NM_001407746.1:c.4820C>T NP_001394675.1:p.Ser1607Phe missense NM_001407747.1:c.4820C>T NP_001394676.1:p.Ser1607Phe missense NM_001407748.1:c.4820C>T NP_001394677.1:p.Ser1607Phe missense NM_001407749.1:c.4820C>T NP_001394678.1:p.Ser1607Phe missense NM_001407750.1:c.4820C>T NP_001394679.1:p.Ser1607Phe missense NM_001407751.1:c.4820C>T NP_001394680.1:p.Ser1607Phe missense NM_001407752.1:c.4820C>T NP_001394681.1:p.Ser1607Phe missense NM_001407838.1:c.4817C>T NP_001394767.1:p.Ser1606Phe missense NM_001407839.1:c.4817C>T NP_001394768.1:p.Ser1606Phe missense NM_001407841.1:c.4817C>T NP_001394770.1:p.Ser1606Phe missense NM_001407842.1:c.4817C>T NP_001394771.1:p.Ser1606Phe missense NM_001407843.1:c.4817C>T NP_001394772.1:p.Ser1606Phe missense NM_001407844.1:c.4817C>T NP_001394773.1:p.Ser1606Phe missense NM_001407845.1:c.4817C>T NP_001394774.1:p.Ser1606Phe missense NM_001407846.1:c.4817C>T NP_001394775.1:p.Ser1606Phe missense NM_001407847.1:c.4817C>T NP_001394776.1:p.Ser1606Phe missense NM_001407848.1:c.4817C>T NP_001394777.1:p.Ser1606Phe missense NM_001407849.1:c.4817C>T NP_001394778.1:p.Ser1606Phe missense NM_001407850.1:c.4817C>T NP_001394779.1:p.Ser1606Phe missense NM_001407851.1:c.4817C>T NP_001394780.1:p.Ser1606Phe missense NM_001407852.1:c.4817C>T NP_001394781.1:p.Ser1606Phe missense NM_001407853.1:c.4817C>T NP_001394782.1:p.Ser1606Phe missense NM_001407854.1:c.4964C>T NP_001394783.1:p.Ser1655Phe missense NM_001407858.1:c.4961C>T NP_001394787.1:p.Ser1654Phe missense NM_001407859.1:c.4961C>T NP_001394788.1:p.Ser1654Phe missense NM_001407860.1:c.4961C>T NP_001394789.1:p.Ser1654Phe missense NM_001407861.1:c.4958C>T NP_001394790.1:p.Ser1653Phe missense NM_001407862.1:c.4763C>T NP_001394791.1:p.Ser1588Phe missense NM_001407863.1:c.4838C>T NP_001394792.1:p.Ser1613Phe missense NM_001407874.1:c.4757C>T NP_001394803.1:p.Ser1586Phe missense NM_001407875.1:c.4757C>T NP_001394804.1:p.Ser1586Phe missense NM_001407879.1:c.4754C>T NP_001394808.1:p.Ser1585Phe missense NM_001407881.1:c.4754C>T NP_001394810.1:p.Ser1585Phe missense NM_001407882.1:c.4754C>T NP_001394811.1:p.Ser1585Phe missense NM_001407884.1:c.4754C>T NP_001394813.1:p.Ser1585Phe missense NM_001407885.1:c.4754C>T NP_001394814.1:p.Ser1585Phe missense NM_001407886.1:c.4754C>T NP_001394815.1:p.Ser1585Phe missense NM_001407887.1:c.4754C>T NP_001394816.1:p.Ser1585Phe missense NM_001407889.1:c.4754C>T NP_001394818.1:p.Ser1585Phe missense NM_001407894.1:c.4751C>T NP_001394823.1:p.Ser1584Phe missense NM_001407895.1:c.4751C>T NP_001394824.1:p.Ser1584Phe missense NM_001407896.1:c.4751C>T NP_001394825.1:p.Ser1584Phe missense NM_001407897.1:c.4751C>T NP_001394826.1:p.Ser1584Phe missense NM_001407898.1:c.4751C>T NP_001394827.1:p.Ser1584Phe missense NM_001407899.1:c.4751C>T NP_001394828.1:p.Ser1584Phe missense NM_001407900.1:c.4751C>T NP_001394829.1:p.Ser1584Phe missense NM_001407902.1:c.4751C>T NP_001394831.1:p.Ser1584Phe missense NM_001407904.1:c.4751C>T NP_001394833.1:p.Ser1584Phe missense NM_001407906.1:c.4751C>T NP_001394835.1:p.Ser1584Phe missense NM_001407907.1:c.4751C>T NP_001394836.1:p.Ser1584Phe missense NM_001407908.1:c.4751C>T NP_001394837.1:p.Ser1584Phe missense NM_001407909.1:c.4751C>T NP_001394838.1:p.Ser1584Phe missense NM_001407910.1:c.4751C>T NP_001394839.1:p.Ser1584Phe missense NM_001407915.1:c.4748C>T NP_001394844.1:p.Ser1583Phe missense NM_001407916.1:c.4748C>T NP_001394845.1:p.Ser1583Phe missense NM_001407917.1:c.4748C>T NP_001394846.1:p.Ser1583Phe missense NM_001407918.1:c.4748C>T NP_001394847.1:p.Ser1583Phe missense NM_001407919.1:c.4841C>T NP_001394848.1:p.Ser1614Phe missense NM_001407920.1:c.4700C>T NP_001394849.1:p.Ser1567Phe missense NM_001407921.1:c.4700C>T NP_001394850.1:p.Ser1567Phe missense NM_001407922.1:c.4700C>T NP_001394851.1:p.Ser1567Phe missense NM_001407923.1:c.4700C>T NP_001394852.1:p.Ser1567Phe missense NM_001407924.1:c.4700C>T NP_001394853.1:p.Ser1567Phe missense NM_001407925.1:c.4700C>T NP_001394854.1:p.Ser1567Phe missense NM_001407926.1:c.4700C>T NP_001394855.1:p.Ser1567Phe missense NM_001407927.1:c.4697C>T NP_001394856.1:p.Ser1566Phe missense NM_001407928.1:c.4697C>T NP_001394857.1:p.Ser1566Phe missense NM_001407929.1:c.4697C>T NP_001394858.1:p.Ser1566Phe missense NM_001407930.1:c.4697C>T NP_001394859.1:p.Ser1566Phe missense NM_001407931.1:c.4697C>T NP_001394860.1:p.Ser1566Phe missense NM_001407932.1:c.4697C>T NP_001394861.1:p.Ser1566Phe missense NM_001407933.1:c.4697C>T NP_001394862.1:p.Ser1566Phe missense NM_001407934.1:c.4694C>T NP_001394863.1:p.Ser1565Phe missense NM_001407935.1:c.4694C>T NP_001394864.1:p.Ser1565Phe missense NM_001407936.1:c.4694C>T NP_001394865.1:p.Ser1565Phe missense NM_001407937.1:c.4841C>T NP_001394866.1:p.Ser1614Phe missense NM_001407938.1:c.4841C>T NP_001394867.1:p.Ser1614Phe missense NM_001407939.1:c.4838C>T NP_001394868.1:p.Ser1613Phe missense NM_001407940.1:c.4838C>T NP_001394869.1:p.Ser1613Phe missense NM_001407941.1:c.4835C>T NP_001394870.1:p.Ser1612Phe missense NM_001407942.1:c.4823C>T NP_001394871.1:p.Ser1608Phe missense NM_001407943.1:c.4820C>T NP_001394872.1:p.Ser1607Phe missense NM_001407944.1:c.4820C>T NP_001394873.1:p.Ser1607Phe missense NM_001407945.1:c.4820C>T NP_001394874.1:p.Ser1607Phe missense NM_001407946.1:c.4631C>T NP_001394875.1:p.Ser1544Phe missense NM_001407947.1:c.4631C>T NP_001394876.1:p.Ser1544Phe missense NM_001407948.1:c.4631C>T NP_001394877.1:p.Ser1544Phe missense NM_001407949.1:c.4631C>T NP_001394878.1:p.Ser1544Phe missense NM_001407950.1:c.4628C>T NP_001394879.1:p.Ser1543Phe missense NM_001407951.1:c.4628C>T NP_001394880.1:p.Ser1543Phe missense NM_001407952.1:c.4628C>T NP_001394881.1:p.Ser1543Phe missense NM_001407953.1:c.4628C>T NP_001394882.1:p.Ser1543Phe missense NM_001407954.1:c.4628C>T NP_001394883.1:p.Ser1543Phe missense NM_001407955.1:c.4628C>T NP_001394884.1:p.Ser1543Phe missense NM_001407956.1:c.4625C>T NP_001394885.1:p.Ser1542Phe missense NM_001407957.1:c.4625C>T NP_001394886.1:p.Ser1542Phe missense NM_001407958.1:c.4625C>T NP_001394887.1:p.Ser1542Phe missense NM_001407959.1:c.4583C>T NP_001394888.1:p.Ser1528Phe missense NM_001407960.1:c.4580C>T NP_001394889.1:p.Ser1527Phe missense NM_001407962.1:c.4580C>T NP_001394891.1:p.Ser1527Phe missense NM_001407963.1:c.4577C>T NP_001394892.1:p.Ser1526Phe missense NM_001407964.1:c.4502C>T NP_001394893.1:p.Ser1501Phe missense NM_001407965.1:c.4457C>T NP_001394894.1:p.Ser1486Phe missense NM_001407966.1:c.4076C>T NP_001394895.1:p.Ser1359Phe missense NM_001407967.1:c.4073C>T NP_001394896.1:p.Ser1358Phe missense NM_001407968.1:c.2360C>T NP_001394897.1:p.Ser787Phe missense NM_001407969.1:c.2357C>T NP_001394898.1:p.Ser786Phe missense NM_001407970.1:c.1721C>T NP_001394899.1:p.Ser574Phe missense NM_001407971.1:c.1721C>T NP_001394900.1:p.Ser574Phe missense NM_001407972.1:c.1718C>T NP_001394901.1:p.Ser573Phe missense NM_001407973.1:c.1655C>T NP_001394902.1:p.Ser552Phe missense NM_001407974.1:c.1655C>T NP_001394903.1:p.Ser552Phe missense NM_001407975.1:c.1655C>T NP_001394904.1:p.Ser552Phe missense NM_001407976.1:c.1655C>T NP_001394905.1:p.Ser552Phe missense NM_001407977.1:c.1655C>T NP_001394906.1:p.Ser552Phe missense NM_001407978.1:c.1655C>T NP_001394907.1:p.Ser552Phe missense NM_001407979.1:c.1652C>T NP_001394908.1:p.Ser551Phe missense NM_001407980.1:c.1652C>T NP_001394909.1:p.Ser551Phe missense NM_001407981.1:c.1652C>T NP_001394910.1:p.Ser551Phe missense NM_001407982.1:c.1652C>T NP_001394911.1:p.Ser551Phe missense NM_001407983.1:c.1652C>T NP_001394912.1:p.Ser551Phe missense NM_001407984.1:c.1652C>T NP_001394913.1:p.Ser551Phe missense NM_001407985.1:c.1652C>T NP_001394914.1:p.Ser551Phe missense NM_001407986.1:c.1652C>T NP_001394915.1:p.Ser551Phe missense NM_001407990.1:c.1652C>T NP_001394919.1:p.Ser551Phe missense NM_001407991.1:c.1652C>T NP_001394920.1:p.Ser551Phe missense NM_001407992.1:c.1652C>T NP_001394921.1:p.Ser551Phe missense NM_001407993.1:c.1652C>T NP_001394922.1:p.Ser551Phe missense NM_001408392.1:c.1649C>T NP_001395321.1:p.Ser550Phe missense NM_001408396.1:c.1649C>T NP_001395325.1:p.Ser550Phe missense NM_001408397.1:c.1649C>T NP_001395326.1:p.Ser550Phe missense NM_001408398.1:c.1649C>T NP_001395327.1:p.Ser550Phe missense NM_001408399.1:c.1649C>T NP_001395328.1:p.Ser550Phe missense NM_001408400.1:c.1649C>T NP_001395329.1:p.Ser550Phe missense NM_001408401.1:c.1649C>T NP_001395330.1:p.Ser550Phe missense NM_001408402.1:c.1649C>T NP_001395331.1:p.Ser550Phe missense NM_001408403.1:c.1649C>T NP_001395332.1:p.Ser550Phe missense NM_001408404.1:c.1649C>T NP_001395333.1:p.Ser550Phe missense NM_001408406.1:c.1646C>T NP_001395335.1:p.Ser549Phe missense NM_001408407.1:c.1646C>T NP_001395336.1:p.Ser549Phe missense NM_001408408.1:c.1646C>T NP_001395337.1:p.Ser549Phe missense NM_001408409.1:c.1643C>T NP_001395338.1:p.Ser548Phe missense NM_001408410.1:c.1580C>T NP_001395339.1:p.Ser527Phe missense NM_001408411.1:c.1577C>T NP_001395340.1:p.Ser526Phe missense NM_001408412.1:c.1574C>T NP_001395341.1:p.Ser525Phe missense NM_001408413.1:c.1574C>T NP_001395342.1:p.Ser525Phe missense NM_001408414.1:c.1574C>T NP_001395343.1:p.Ser525Phe missense NM_001408415.1:c.1574C>T NP_001395344.1:p.Ser525Phe missense NM_001408416.1:c.1574C>T NP_001395345.1:p.Ser525Phe missense NM_001408418.1:c.1538C>T NP_001395347.1:p.Ser513Phe missense NM_001408419.1:c.1538C>T NP_001395348.1:p.Ser513Phe missense NM_001408420.1:c.1538C>T NP_001395349.1:p.Ser513Phe missense NM_001408421.1:c.1535C>T NP_001395350.1:p.Ser512Phe missense NM_001408422.1:c.1535C>T NP_001395351.1:p.Ser512Phe missense NM_001408423.1:c.1535C>T NP_001395352.1:p.Ser512Phe missense NM_001408424.1:c.1535C>T NP_001395353.1:p.Ser512Phe missense NM_001408425.1:c.1532C>T NP_001395354.1:p.Ser511Phe missense NM_001408426.1:c.1532C>T NP_001395355.1:p.Ser511Phe missense NM_001408427.1:c.1532C>T NP_001395356.1:p.Ser511Phe missense NM_001408428.1:c.1532C>T NP_001395357.1:p.Ser511Phe missense NM_001408429.1:c.1532C>T NP_001395358.1:p.Ser511Phe missense NM_001408430.1:c.1532C>T NP_001395359.1:p.Ser511Phe missense NM_001408431.1:c.1532C>T NP_001395360.1:p.Ser511Phe missense NM_001408432.1:c.1529C>T NP_001395361.1:p.Ser510Phe missense NM_001408433.1:c.1529C>T NP_001395362.1:p.Ser510Phe missense NM_001408434.1:c.1529C>T NP_001395363.1:p.Ser510Phe missense NM_001408435.1:c.1529C>T NP_001395364.1:p.Ser510Phe missense NM_001408436.1:c.1529C>T NP_001395365.1:p.Ser510Phe missense NM_001408437.1:c.1529C>T NP_001395366.1:p.Ser510Phe missense NM_001408438.1:c.1529C>T NP_001395367.1:p.Ser510Phe missense NM_001408439.1:c.1529C>T NP_001395368.1:p.Ser510Phe missense NM_001408440.1:c.1529C>T NP_001395369.1:p.Ser510Phe missense NM_001408441.1:c.1529C>T NP_001395370.1:p.Ser510Phe missense NM_001408442.1:c.1529C>T NP_001395371.1:p.Ser510Phe missense NM_001408443.1:c.1529C>T NP_001395372.1:p.Ser510Phe missense NM_001408444.1:c.1529C>T NP_001395373.1:p.Ser510Phe missense NM_001408445.1:c.1526C>T NP_001395374.1:p.Ser509Phe missense NM_001408446.1:c.1526C>T NP_001395375.1:p.Ser509Phe missense NM_001408447.1:c.1526C>T NP_001395376.1:p.Ser509Phe missense NM_001408448.1:c.1526C>T NP_001395377.1:p.Ser509Phe missense NM_001408450.1:c.1526C>T NP_001395379.1:p.Ser509Phe missense NM_001408451.1:c.1520C>T NP_001395380.1:p.Ser507Phe missense NM_001408452.1:c.1514C>T NP_001395381.1:p.Ser505Phe missense NM_001408453.1:c.1514C>T NP_001395382.1:p.Ser505Phe missense NM_001408454.1:c.1514C>T NP_001395383.1:p.Ser505Phe missense NM_001408455.1:c.1514C>T NP_001395384.1:p.Ser505Phe missense NM_001408456.1:c.1514C>T NP_001395385.1:p.Ser505Phe missense NM_001408457.1:c.1514C>T NP_001395386.1:p.Ser505Phe missense NM_001408458.1:c.1511C>T NP_001395387.1:p.Ser504Phe missense NM_001408459.1:c.1511C>T NP_001395388.1:p.Ser504Phe missense NM_001408460.1:c.1511C>T NP_001395389.1:p.Ser504Phe missense NM_001408461.1:c.1511C>T NP_001395390.1:p.Ser504Phe missense NM_001408462.1:c.1511C>T NP_001395391.1:p.Ser504Phe missense NM_001408463.1:c.1511C>T NP_001395392.1:p.Ser504Phe missense NM_001408464.1:c.1511C>T NP_001395393.1:p.Ser504Phe missense NM_001408465.1:c.1511C>T NP_001395394.1:p.Ser504Phe missense NM_001408466.1:c.1511C>T NP_001395395.1:p.Ser504Phe missense NM_001408467.1:c.1511C>T NP_001395396.1:p.Ser504Phe missense NM_001408468.1:c.1508C>T NP_001395397.1:p.Ser503Phe missense NM_001408469.1:c.1508C>T NP_001395398.1:p.Ser503Phe missense NM_001408470.1:c.1508C>T NP_001395399.1:p.Ser503Phe missense NM_001408472.1:c.1652C>T NP_001395401.1:p.Ser551Phe missense NM_001408473.1:c.1649C>T NP_001395402.1:p.Ser550Phe missense NM_001408474.1:c.1454C>T NP_001395403.1:p.Ser485Phe missense NM_001408475.1:c.1451C>T NP_001395404.1:p.Ser484Phe missense NM_001408476.1:c.1451C>T NP_001395405.1:p.Ser484Phe missense NM_001408478.1:c.1445C>T NP_001395407.1:p.Ser482Phe missense NM_001408479.1:c.1445C>T NP_001395408.1:p.Ser482Phe missense NM_001408480.1:c.1445C>T NP_001395409.1:p.Ser482Phe missense NM_001408481.1:c.1442C>T NP_001395410.1:p.Ser481Phe missense NM_001408482.1:c.1442C>T NP_001395411.1:p.Ser481Phe missense NM_001408483.1:c.1442C>T NP_001395412.1:p.Ser481Phe missense NM_001408484.1:c.1442C>T NP_001395413.1:p.Ser481Phe missense NM_001408485.1:c.1442C>T NP_001395414.1:p.Ser481Phe missense NM_001408489.1:c.1442C>T NP_001395418.1:p.Ser481Phe missense NM_001408490.1:c.1442C>T NP_001395419.1:p.Ser481Phe missense NM_001408491.1:c.1442C>T NP_001395420.1:p.Ser481Phe missense NM_001408492.1:c.1439C>T NP_001395421.1:p.Ser480Phe missense NM_001408493.1:c.1439C>T NP_001395422.1:p.Ser480Phe missense NM_001408494.1:c.1415C>T NP_001395423.1:p.Ser472Phe missense NM_001408495.1:c.1409C>T NP_001395424.1:p.Ser470Phe missense NM_001408496.1:c.1391C>T NP_001395425.1:p.Ser464Phe missense NM_001408497.1:c.1391C>T NP_001395426.1:p.Ser464Phe missense NM_001408498.1:c.1391C>T NP_001395427.1:p.Ser464Phe missense NM_001408499.1:c.1391C>T NP_001395428.1:p.Ser464Phe missense NM_001408500.1:c.1391C>T NP_001395429.1:p.Ser464Phe missense NM_001408501.1:c.1391C>T NP_001395430.1:p.Ser464Phe missense NM_001408502.1:c.1388C>T NP_001395431.1:p.Ser463Phe missense NM_001408503.1:c.1388C>T NP_001395432.1:p.Ser463Phe missense NM_001408504.1:c.1388C>T NP_001395433.1:p.Ser463Phe missense NM_001408505.1:c.1385C>T NP_001395434.1:p.Ser462Phe missense NM_001408506.1:c.1328C>T NP_001395435.1:p.Ser443Phe missense NM_001408507.1:c.1325C>T NP_001395436.1:p.Ser442Phe missense NM_001408508.1:c.1316C>T NP_001395437.1:p.Ser439Phe missense NM_001408509.1:c.1313C>T NP_001395438.1:p.Ser438Phe missense NM_001408510.1:c.1274C>T NP_001395439.1:p.Ser425Phe missense NM_001408511.1:c.1271C>T NP_001395440.1:p.Ser424Phe missense NM_001408512.1:c.1151C>T NP_001395441.1:p.Ser384Phe missense NM_001408513.1:c.1124C>T NP_001395442.1:p.Ser375Phe missense NM_007297.4:c.4823C>T NP_009228.2:p.Ser1608Phe missense NM_007298.4:c.1652C>T NP_009229.2:p.Ser551Phe missense NM_007299.4:c.1652C>T NP_009230.2:p.Ser551Phe missense NM_007300.4:c.5027C>T NP_009231.2:p.Ser1676Phe missense NM_007304.2:c.1652C>T NP_009235.2:p.Ser551Phe missense NR_027676.2:n.5141C>T non-coding transcript variant NC_000017.11:g.43070950G>A NC_000017.10:g.41222967G>A NG_005905.2:g.147034C>T LRG_292:g.147034C>T LRG_292t1:c.4964C>T LRG_292p1:p.Ser1655Phe P38398:p.Ser1655Phe U14680.1:n.5083C>T - Protein change
- S1655F, S1676F, S551F, S1608F, S1358F, S1526F, S1567F, S1654F, S384F, S439F, S463F, S481F, S482F, S485F, S507F, S509F, S512F, S525F, S550F, S574F, S442F, S443F, S462F, S470F, S472F, S484F, S504F, S526F, S549F, S552F, S1501F, S1542F, S1566F, S1583F, S1584F, S1607F, S1635F, S1636F, S1652F, S1675F, S438F, S1359F, S1527F, S1528F, S1585F, S1586F, S1588F, S1606F, S1613F, S1614F, S1628F, S1653F, S425F, S464F, S480F, S511F, S787F, S1486F, S1543F, S1544F, S1565F, S1611F, S1612F, S1627F, S1629F, S1650F, S1651F, S1677F, S375F, S424F, S503F, S505F, S510F, S513F, S527F, S548F, S573F, S786F
- Other names
- -
- Canonical SPDI
- NC_000017.11:43070949:G:A
-
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.4964C>T, a MISSENSE variant, produced a function score of -1.56, 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 |
13050 | 14856 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 27, 2024 | RCV000112436.15 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 18, 2020 | RCV000223580.12 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 12, 2022 | RCV000709466.21 | |
| Pathogenic (2) |
no assertion criteria provided
|
- | RCV001528321.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162417.8 |
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
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary Breast and Ovarian Cancer
Affected status: yes
Allele origin:
germline
|
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV000897862.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
Data included in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing … (more)
Data included in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 0.04 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on SIFT, Align GVGD and Polyphen HumVar (PP3). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018), an assay well validated against ENIGMA/ClinVar (PS3) The variant is located in the BRCT1 domain (PM1_sup). c.4963T>C p.(Ser1655Pro) previously classified as pathogenic by CanVIG (July 2018) (PM5). Data not included in classification: Extensive additional functional data demonstrating variant to be deleterious: Williams et al. Carvalho et al. Lee et al., Bouwman et al (2013), Domchek et al (2013), Shakya (2011). Anantha et al (2017) elife; 6 e21350 Apr: undertook functional studies confirming reduced HR activity. Computer based algorithms predicting variant to be deleterious: Iverson (2012), Gomez-Garcia (2009) and Karchin (2007). Segregation 1 in 4 in UK family. Gomez-Garcia et al (2009) demonstrated segregation in 6/6 individuals (across 2 families) but no further details provided. There are additional reports of this variant in ClinVar (2), BIC (3) and BRCA1 LOVD (11). (less)
Number of individuals with the variant: 2
Sex: female
Geographic origin: United Kingdom
Testing laboratory: UK Molecular Diagnostic Labs
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Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140497.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(Jan 21, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001478730.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Comment:
Variant summary: BRCA1 c.4964C>T (p.Ser1655Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: BRCA1 c.4964C>T (p.Ser1655Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250710 control chromosomes. c.4964C>T has been widely reported in the literature and subsequently cited by others to co-segregate with disease in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer (example, Gomez_Garcia_2009), as an isolated occurrence in a proband reporting a positive history of breast cancer (example, Cotrim_2019), and isolated reports in individuals with breast cancer (example, Inagaki-Kawata_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bouwman_2020, Findlay_2018). The most pronounced variant effect results in defective homologous recombination DNA repair activity in independent measures of evaluation. Multiple clinical diagnostic laboratories and one cancer variant interpretation group have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Dec 12, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001579488.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15133502, 15133503, 17308087, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15133502, 15133503, 17308087, 20516115, 23867111, 28398198). 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: 55333). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19200354, 19563646, 24249303, 27767231, 29176636). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1655 of the BRCA1 protein (p.Ser1655Phe). (less)
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Pathogenic
(May 27, 2024)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005045933.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
PP3; PS3; PP1_Strong; PM2_Supporting
|
|
|
Likely pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: research
|
Hereditary breast ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
|
Genetics Program, Instituto Nacional de Cancer
Accession: SCV002515223.1
First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022 |
Geographic origin: Brazil
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Pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 1
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV004042786.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
ACMG criteria used to clasify this variant:PS3, PS4, PM2_SUP, PP1
|
|
|
Likely pathogenic
(Aug 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000277296.5
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.S1655F variant (also known as c.4964C>T), located in coding exon 14 of the BRCA1 gene, results from a C to T substitution at nucleotide … (more)
The p.S1655F variant (also known as c.4964C>T), located in coding exon 14 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4964. The serine at codon 1655 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome (HBOC) (Gómez García et al. Breast Cancer Res. 2009; 11(1):1-12; Mohammadi et al. BMC Cancer. 2009; 9:211; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4). Results from two different functional studies showed this variant results in abrogation of transcriptional activation function of the protein (Carvalho et al. Cancer Res. 2007; 67(4):1494-501; Lee MS et al. Cancer Res. 2010; 70(12):4880-90; Bouwman P et al. Cancer Discov. 2013; 3(10):1142-55). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Experimental results from three independent studies showed that the p.S1655 residue is part of the hydrophobic phosphopeptide binding pocket of the BRCA1 protein which mediates interactions of the BRCA1 protein with various phosphopeptides in order to perform the transactivation function of the protein (Williams RS et al. Nat Struct Mol Biol. 2004; 11(6):519-25; Shiozaki et al. Mol Cell. 2004; 4(3):405-12; Lee MS et al. Cancer Res. 2010; 70(12):4880-90). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is predicted to be highly destabilizing to the local structure (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
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Uncertain significance
(May 29, 2002)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 1
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA1)
Accession: SCV000145224.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Asian
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
|
|
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758199.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739871.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957115.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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not provided
(-)
|
no classification provided
Method: in vitro
|
Breast-ovarian cancer, familial 1
Affected status: not applicable
Allele origin:
not applicable
|
Brotman Baty Institute, University of Washington
Accession: SCV001243277.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
Method: saturation genome editing in haploid cells
Result:
LOSS_OF_FUNCTION:-1.55569687050806
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| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: BRCA1 c.4964C>T (p.Ser1655Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250710 control chromosomes. c.4964C>T has been widely reported in the literature and subsequently cited by others to co-segregate with disease in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer (example, Gomez_Garcia_2009), as an isolated occurrence in a proband reporting a positive history of breast cancer (example, Cotrim_2019), and isolated reports in individuals with breast cancer (example, Inagaki-Kawata_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bouwman_2020, Findlay_2018). The most pronounced variant effect results in defective homologous recombination DNA repair activity in independent measures of evaluation. Multiple clinical diagnostic laboratories and one cancer variant interpretation group have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15133502, 15133503, 17308087, 20516115, 23867111, 28398198). 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: 55333). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19200354, 19563646, 24249303, 27767231, 29176636). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1655 of the BRCA1 protein (p.Ser1655Phe).
Comment:
PP3; PS3; PP1_Strong; PM2_Supporting
Comment:
ACMG criteria used to clasify this variant:PS3, PS4, PM2_SUP, PP1
Comment:
The p.S1655F variant (also known as c.4964C>T), located in coding exon 14 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4964. The serine at codon 1655 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome (HBOC) (Gómez García et al. Breast Cancer Res. 2009; 11(1):1-12; Mohammadi et al. BMC Cancer. 2009; 9:211; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4). Results from two different functional studies showed this variant results in abrogation of transcriptional activation function of the protein (Carvalho et al. Cancer Res. 2007; 67(4):1494-501; Lee MS et al. Cancer Res. 2010; 70(12):4880-90; Bouwman P et al. Cancer Discov. 2013; 3(10):1142-55). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Experimental results from three independent studies showed that the p.S1655 residue is part of the hydrophobic phosphopeptide binding pocket of the BRCA1 protein which mediates interactions of the BRCA1 protein with various phosphopeptides in order to perform the transactivation function of the protein (Williams RS et al. Nat Struct Mol Biol. 2004; 11(6):519-25; Shiozaki et al. Mol Cell. 2004; 4(3):405-12; Lee MS et al. Cancer Res. 2010; 70(12):4880-90). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is predicted to be highly destabilizing to the local structure (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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. |
|---|---|---|---|---|
|
functionally_abnormal
|
Method citation(s):
|
|
Brotman Baty Institute, University of Washington
Accession: SCV001243277.1
|
Comment:
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.4964C>T, a MISSENSE variant, produced a function score of -1.56, corresponding to a functional classification of LOSS_OF_FUNCTION. … (more)
The saturation genome editing (SGE) assay for BRCA1 NM_007294.3:c.4964C>T, a MISSENSE variant, produced a function score of -1.56, 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)
|
Comment:
Data included in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 0.04 (PS4). The variant is absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Predicted deleterious on SIFT, Align GVGD and Polyphen HumVar (PP3). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018), an assay well validated against ENIGMA/ClinVar (PS3) The variant is located in the BRCT1 domain (PM1_sup). c.4963T>C p.(Ser1655Pro) previously classified as pathogenic by CanVIG (July 2018) (PM5). Data not included in classification: Extensive additional functional data demonstrating variant to be deleterious: Williams et al. Carvalho et al. Lee et al., Bouwman et al (2013), Domchek et al (2013), Shakya (2011). Anantha et al (2017) elife; 6 e21350 Apr: undertook functional studies confirming reduced HR activity. Computer based algorithms predicting variant to be deleterious: Iverson (2012), Gomez-Garcia (2009) and Karchin (2007). Segregation 1 in 4 in UK family. Gomez-Garcia et al (2009) demonstrated segregation in 6/6 individuals (across 2 families) but no further details provided. There are additional reports of this variant in ClinVar (2), BIC (3) and BRCA1 LOVD (11).
Comment:
Variant summary: BRCA1 c.4964C>T (p.Ser1655Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250710 control chromosomes. c.4964C>T has been widely reported in the literature and subsequently cited by others to co-segregate with disease in multiple individuals from families affected with Hereditary Breast And Ovarian Cancer (example, Gomez_Garcia_2009), as an isolated occurrence in a proband reporting a positive history of breast cancer (example, Cotrim_2019), and isolated reports in individuals with breast cancer (example, Inagaki-Kawata_2020). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bouwman_2020, Findlay_2018). The most pronounced variant effect results in defective homologous recombination DNA repair activity in independent measures of evaluation. Multiple clinical diagnostic laboratories and one cancer variant interpretation group have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15133502, 15133503, 17308087, 20516115, 23867111, 28398198). 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: 55333). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19200354, 19563646, 24249303, 27767231, 29176636). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1655 of the BRCA1 protein (p.Ser1655Phe).
Comment:
PP3; PS3; PP1_Strong; PM2_Supporting
Comment:
ACMG criteria used to clasify this variant:PS3, PS4, PM2_SUP, PP1
Comment:
The p.S1655F variant (also known as c.4964C>T), located in coding exon 14 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4964. The serine at codon 1655 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Hereditary Breast and Ovarian Cancer syndrome (HBOC) (Gómez García et al. Breast Cancer Res. 2009; 11(1):1-12; Mohammadi et al. BMC Cancer. 2009; 9:211; Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4). Results from two different functional studies showed this variant results in abrogation of transcriptional activation function of the protein (Carvalho et al. Cancer Res. 2007; 67(4):1494-501; Lee MS et al. Cancer Res. 2010; 70(12):4880-90; Bouwman P et al. Cancer Discov. 2013; 3(10):1142-55). An additional functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Experimental results from three independent studies showed that the p.S1655 residue is part of the hydrophobic phosphopeptide binding pocket of the BRCA1 protein which mediates interactions of the BRCA1 protein with various phosphopeptides in order to perform the transactivation function of the protein (Williams RS et al. Nat Struct Mol Biol. 2004; 11(6):519-25; Shiozaki et al. Mol Cell. 2004; 4(3):405-12; Lee MS et al. Cancer Res. 2010; 70(12):4880-90). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is predicted to be highly destabilizing to the local structure (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service. | Matta BP | Scientific reports | 2022 | PMID: 36329109 |
| Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants. | Inagaki-Kawata Y | Communications biology | 2020 | PMID: 33067557 |
| Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays. | Bouwman P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2020 | PMID: 32546644 |
| 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 |
| Prevalence of BRCA1 and BRCA2 pathogenic and likely pathogenic variants in non-selected ovarian carcinoma patients in Brazil. | Cotrim DP | BMC cancer | 2019 | PMID: 30606148 |
| Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance. | Langerud J | Human genomics | 2018 | PMID: 30458859 |
| Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
| Accurate classification of BRCA1 variants with saturation genome editing. | Findlay GM | Nature | 2018 | PMID: 30209399 |
| Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan. | Arai M | Journal of human genetics | 2018 | PMID: 29176636 |
| Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. | Anantha RW | eLife | 2017 | PMID: 28398198 |
| Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. | Weren RD | Human mutation | 2017 | PMID: 27767231 |
| Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. | Nakamura S | Breast cancer (Tokyo, Japan) | 2015 | PMID: 24249303 |
| A high-throughput functional complementation assay for classification of BRCA1 missense variants. | Bouwman P | Cancer discovery | 2013 | PMID: 23867111 |
| Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. | Lee MS | Cancer research | 2010 | PMID: 20516115 |
| A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example. | Mohammadi L | BMC cancer | 2009 | PMID: 19563646 |
| A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. | Gómez García EB | Breast cancer research : BCR | 2009 | PMID: 19200354 |
| Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. | Carvalho MA | Cancer research | 2007 | PMID: 17308087 |
| Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. | Abkevich V | Journal of medical genetics | 2004 | PMID: 15235020 |
| Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. | Williams RS | Nature structural & molecular biology | 2004 | PMID: 15133503 |
| Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. | Clapperton JA | Nature structural & molecular biology | 2004 | PMID: 15133502 |
| https://sge.gs.washington.edu/BRCA1/ | - | - | - | - |
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Text-mined citations for rs80357390 ...
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 Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.