ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.508C>T (p.Arg170Trp) (rs80357325)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048786 SCV000076799 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 170 of the BRCA1 protein (p.Arg170Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80357325, ExAC 0.006%) but has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 55393). Experimental studies have shown that BRCA1 harboring this missense change restores the proliferation defect and cisplatin sensitivity of BRCA1-null mouse embryonic cells  (PMID: 23867111). In summary, this variant is a rare missense change that has not been shown to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000132127 SCV000187195 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000483759 SCV000566762 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.508C>T at the cDNA level, p.Arg170Trp (R170W) 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 627C>T. This variant has been observed in at least one individual with breast cancer and a family history of breast and/or ovarian cancer (Tung 2015). Functional studies by Bouwman et al. (2013) have suggested that BRCA1 Arg170Trp is neutral based on insensitivity to cisplatin and ability to support growth similar to controls in BRCA1-deficient mouse embryonic stem cells. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Arg170Trp is located in the BRD7 binding domain (Harte 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Arg170Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000112723 SCV000784865 uncertain significance Breast-ovarian cancer, familial 1 2017-01-18 criteria provided, single submitter clinical testing
Color RCV000132127 SCV000911724 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112723 SCV000145603 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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