ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5509T>C (p.Trp1837Arg) (rs80356959)

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Total submissions: 13
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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 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 2019-08-09 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). This alteration has been predicted to be deleterious in several other 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). 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 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 likely pathogenic not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5509T>C at the cDNA level, p.Trp1837Arg (W1837R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). Using alternate nomenclature, this variant has been previously published as BRCA1 5628T>C. This variant has been observed in at least three individuals with a personal and/or family history of early-onset breast cancer (Montagna 1996, Meindl 2002, Phelan 2005). Segregation analysis was performed in the kindred reported by Phelan et al. (2005); however, an insufficient number of individuals were tested to draw definitive conclusions regarding this variantÂ’s interpretation. Functional analyses have consistently found BRCA1 Trp1837Arg to decrease transactivation activity and destabilize the BRCA1 protein, supporting a deleterious effect (Williams 2003, Phelan 2005, Lee 2010, Rowling 2010). BRCA1 Trp1837Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Trp1837Arg occurs at a position that is conserved through mammals and is located within the BRCT 2 domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Trp1837Arg to be a likely pathogenic variant.
Counsyl RCV000031260 SCV000785711 likely pathogenic Breast-ovarian cancer, familial 1 2017-11-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129546 SCV000908978 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779893 SCV000916785 pathogenic Hereditary breast and 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 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 1 2020-04-02 criteria provided, single submitter clinical testing
Invitae RCV000779893 SCV001578228 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 1837 of the BRCA1 protein (p.Trp1837Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with breast cancer (PMID: 28324225, 11802209, 27741520), and shown to segregate with breast and/or ovarian cancer in several families (PMID: 8968102, 15689452, Invitae). ClinVar contains an entry for this variant (Variation ID: 37679). This variant has been reported to affect BRCA1 protein function (PMID: 20516115, 17305420, 23867111, 15689452, 14534301, 30209399). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031260 SCV000053864 likely pathogenic Breast-ovarian cancer, familial 1 2010-11-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031260 SCV000145556 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031260 SCV001243483 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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