ClinVar Miner

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

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Total submissions: 11
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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 2020-05-26 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%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55393). 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 The p.R170W variant (also known as c.508C>T), located in coding exon 6 of the BRCA1 gene, results from a C to T substitution at nucleotide position 508. The arginine at codon 170 is replaced by tryptophan, an amino acid with dissimilar properties. Functional analysis of this alteration using cDNA-based functional complementation assays in mouse embryonic stem cells demonstrated that this alteration resulted in similar proliferation rates as wildtype, and was not deleterious based on cisplatin sensitivity assays (Bouwman P et al. Cancer Discov 2013 Oct; 3(10):1142-55). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000483759 SCV000566762 uncertain significance not provided 2021-08-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast and ovarian cancers (Tung 2015); Published functional studies demonstrate no damaging effect to cell growth, ubiquitination, or sensitivity to cisplatin (Bouwman 2013, Starita 2015); This variant is associated with the following publications: (PMID: 23867111, 25823446, 25186627, 30287823, 33087888, 23983145, 10923033, Rodriguez2013[CaseReport], 31131967)
Counsyl RCV000112723 SCV000784865 uncertain significance Breast-ovarian cancer, familial 1 2017-01-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132127 SCV000911724 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-07 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 170 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported this variant as functional based on growth and homology-directed DNA repair assays in mouse Brca1-null embryonic stem cells (PMID: 23867111, 32546644). This variant has been reported in a multifactorial analysis as benign based in part to tumor pathology and family history likelihood ratios (PMID: 31131967), and has been observed in a large breast cancer case-control study in one unaffected control individual (PMID: 30287823). However, this variant also has been observed in an individual affected with breast cancer who was considered high-risk based on family history (PMID: 25186627). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483759 SCV001133607 uncertain significance not provided 2019-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Research and Development, ARUP Laboratories RCV001664004 SCV001878135 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000112723 SCV000145603 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000483759 SCV001549629 uncertain significance not provided no assertion criteria provided clinical testing

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