ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6541G>C (p.Gly2181Arg) (rs371067421)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205463 SCV000260223 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2181 of the BRCA2 protein (p.Gly2181Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs371067421, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38051). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000420330 SCV000520067 likely benign not specified 2017-08-17 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586226 SCV000600711 uncertain significance not provided 2019-05-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567616 SCV000661404 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000586226 SCV000694979 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6541G>C (p.Gly2181Arg) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. This variant was found in 1/120274 control chromosomes (ExAC) at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Although, multiple reputable databases/clinical diagnostic laboratories have cited the variant with conflicting classifications, "uncertain significance" or "likely benign," without information for an independent evaluation. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
PreventionGenetics,PreventionGenetics RCV000586226 SCV000805747 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing
Color RCV000567616 SCV000911403 likely benign Hereditary cancer-predisposing syndrome 2017-05-22 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031633 SCV000054240 likely benign Breast-ovarian cancer, familial 2 2012-05-21 no assertion criteria provided clinical testing

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