ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.508C>T (p.Arg170Trp) (rs80357325)

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Total submissions: 9
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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) RCV000112723 SCV001161597 benign 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 1 based on posterior probability = 0.000759
Invitae RCV000048786 SCV000076799 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-02 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%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant has been reported not to substantially affect BRCA1 protein function (PMID: 23867111). 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 RCV000132127 SCV000187195 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-28 criteria provided, single submitter clinical testing 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 2019-04-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483759 SCV001133607 uncertain significance not provided 2019-05-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255589 SCV001432091 uncertain significance not specified 2020-08-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.508C>T (p.Arg170Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.508C>T has been reported in the literature in individuals affected with Breast Cancer (example, Tung_2014) as well as an unaffected Japanese male control (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2013). These results showed no damaging effect of this variant based on cisplatin response. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classify the variant as VUS while the expert panel has settled upon a definitive classification as Benign based on posterior probability from multifactorial likelihood analysis (Plon_2008). Based on the evidence outlined above, until the consensus interpretation converges to a neutral/benign outcome, the variant was classified as uncertain significance.
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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