ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.994C>T (p.Arg332Trp) (rs80357176)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049215 SCV000077228 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 332 of the BRCA1 protein (p.Arg332Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 55775). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000132444 SCV000187538 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236122 SCV000292506 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.994C>T at the cDNA level, p.Arg332Trp (R332W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant would be defined as BRCA1 1113C>T. This variant was observed in at least one individual with a personal and/or family history of BRCA-associated cancer (Tarabeux 2014). BRCA1 Arg332Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region of interaction with multiple proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg332Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132444 SCV000683381 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing
Counsyl RCV000111524 SCV000785074 uncertain significance Breast-ovarian cancer, familial 1 2017-04-04 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111524 SCV000143975 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735449 SCV000863585 uncertain significance Breast and/or ovarian cancer 2015-12-03 no assertion criteria provided clinical testing

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