ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.442T>C (p.Cys148Arg) (rs80358677)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044413 SCV000072426 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 148 of the BRCA2 protein (p.Cys148Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs80358677, ExAC 0.009%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51647). 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: Tolerated; PolyPhen-2: Possibly Damaging; 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 RCV000214740 SCV000278058 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-17 criteria provided, single submitter clinical testing The p.C148R variant (also known as c.442T>C), located in coding exon 4 of the BRCA2 gene, results from a T to C substitution at nucleotide position 442. The cysteine at codon 148 is replaced by arginine, an amino acid with highly dissimilar properties. 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 RCV000440751 SCV000523673 likely benign not specified 2016-11-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Health, Inc RCV000214740 SCV000688873 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing This missense variant replaces cysteine with arginine at codon 148 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/250980 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 RCV000985524 SCV001133795 uncertain significance not provided 2020-02-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000440751 SCV001448338 uncertain significance not specified 2020-11-19 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.442T>C (p.Cys148Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250980 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.442T>C has been reported in the literature in at least one individual affected with Breast Cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077325 SCV000109122 uncertain significance Breast-ovarian cancer, familial 2 2008-03-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077325 SCV000146870 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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