ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5509T>C (p.Trp1837Arg)

dbSNP: rs80356959
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031260 SCV001161646 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.991787
Ambry Genetics RCV000129546 SCV000184326 likely pathogenic Hereditary cancer-predisposing syndrome 2022-05-03 criteria provided, single submitter clinical testing The p.W1837R variant (also known as c.5509T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5509. The tryptophan at codon 1837 is replaced by arginine, an amino acid with dissimilar properties. This variant has been seen in multiple ethnically diverse hereditary breast and ovarian cancer (HBOC) syndrome families (Montagna M et al. Cancer Res. 1996;56:5466-9; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zuntini R et al. Front Genet. 2018 Sep;9:378). In one study, p.W1837R was predicted to be a high-risk variant based on decreased transcription levels, segregation, protease sensitivity, and structural analyses. However, pedigree association analysis suggested that this alteration was not causative, and therefore the authors classified this as a VUS due to the conflicting information (Phelan CM et al. J. Med. Genet. 2005;42:138-46). The p.W1837R variant was also predicted to be likely pathogenic based on functional studies showing 3% structural stability, less than 10% protease sensitivity, roughly 20% binding activity, less than 20% binding specificity, and less than 20% transcription activity (Lee MS et al. Cancer Res. 2010;70:4880-90). One 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(7726):217-222). This alteration has been predicted to be deleterious in several other functional and computational studies as well (Williams RS et al. J. Biol. Chem. 2003; 278:53007-16; Abkevich V et al. J. Med. Genet. 2004;41:492-507; Karchin R et al. PLoS Comput. Biol. 2007;3:e26; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Gaiser OJ et al. Biochemistry. 2004 Dec;43:15983-95; Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Woods NT et al. NPJ Genom Med. 2016 Mar). This amino acid position is highly conserved in available vertebrate species. 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.
GeneDx RCV000236322 SCV000292710 pathogenic not provided 2020-01-31 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect: decreased transactivation activity, destabilized BRCA1 protein, and decreased cell survival (Williams 2003, Phelan 2005, Lee 2010, Rowling 2010, Findlay 2018); Observed in several individuals with a personal or family history of BRCA1-related cancers (Montagna 1996, Meindl 2002, Phelan 2005, Fernandes 2016, Cardoso 2018, Fasching 2018, Zuntini 2018); This variant is associated with the following publications: (PMID: 14534301, 30103829, 17305420, 21447777, 16969499, 15235020, 8968102, 23867111, 15689452, 20516115, 15172985, 28781887, 30209399, 30415210, 28111427, 20378548, 18036263, 17005433, 16786532, 16528612, 15609993, 11802209, 29791287, 27741520, 30254663, 28263838, 28324225, 29907814, 29470806, 30765603, 30736435)
Counsyl RCV000031260 SCV000785711 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-11-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129546 SCV000908978 pathogenic Hereditary cancer-predisposing syndrome 2023-08-08 criteria provided, single submitter clinical testing This missense variant replaces tryptophan with arginine at codon 1837 of the BRCA1 protein. Computational models consistently predict deleterious impact of this variant on protein structure and function (PMID: 15172985, 15235020, 15609993, 17305420, 27666373). Functional studies have shown that this variant alters protease sensitivity, structural stability, substrate binding, transcriptional activation, a DNA repair pathway, and sensitivity to chemotherapies (PMID: 14534301, 15689452, 16969499, 17305420, 20378548, 20516115, 21447777, 23867111, 28781887, 30209399, 30765603, 32546644). This variant has been reported in individuals affected with early-onset breast cancer, ovarian cancer, and prostate cancer (PMID: 8968102, 11802209, 15689452, 27741520, 28111427, 28263838, 28324225, 29907814, 29907814, 30103829, 30254663). In three families, the variant was identified in an affected parent and their affected child (PMID: 8968102, 15689452, 30254663). Several probability-based multifactorial likelihood models classify the variant as Pathogenic (PMID: 30415210, 31131967, 32546644). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779893 SCV000916785 pathogenic Hereditary breast ovarian cancer syndrome 2019-03-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5509T>C (p.Trp1837Arg) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Multiple functional studies from different model systems showed mutant protein with decreased stability and solubility, compromised substrate binding activity, increased protease sensitivity, decreased transcription activation level, non-functional HDR pathway and increased cisplatin sensitivity (Phelan_2005, Bouwman_2013, Williams_2003, Lee_ 2010, and Rowling _2010, Findlay_2018), suggesting a defective function of the protein associated with this variant. Structural 3-D modeling study and comparative sequence alignment studies predicted the variant to be cancer-associated or likely to be deleterious (Mirkovic_2004 and Abkevich _2004, respectively). The variant was absent in 247618 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Montagna _1996, Meisel_2017, Fernandes_2016, Zanella_2017, Azzollini_2016, Park_2017, Phelan_2005, Zuntini_2018). In one report, the variant was shown to segregate with disease in two affected family members (Zutini_2018). However, in one family the variant was identified in a father with prostate cancer and in his daughter who had breast cancer at age 39 but it was absent in two cousins of the proband affected with breast and bladder cancer (Phelan_2005), which may suggest lack of co-segregation of the variant with the disease or another pathogenic variant may present in this family. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000031260 SCV001140463 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236322 SCV001469400 pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000031260 SCV001499667 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
Invitae RCV000779893 SCV001578228 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1837 of the BRCA1 protein (p.Trp1837Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8968102, 11802209, 15689452, 27741520, 28324225; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37679). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 15689452, 17305420, 20516115, 23867111, 30209399). For these reasons, this variant has been classified as Pathogenic.
Molecular Endocrinology Laboratory, Christian Medical College RCV000031260 SCV002003983 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 criteria provided, single submitter clinical testing
Baylor Genetics RCV000031260 SCV004215199 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-02-27 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031260 SCV000053864 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2010-11-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031260 SCV000145556 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000031260 SCV001243483 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000236322 SCV001741447 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000236322 SCV001956059 pathogenic not provided no assertion criteria provided clinical testing
Department of Medical and Surgical Sciences, University of Bologna RCV000031260 SCV004228371 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-09-01 no assertion criteria provided clinical testing PS3(Strong)+PM2(Supporting)+PP4(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)

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