ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.517G>C (p.Gly173Arg) (rs397507768)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766596 SCV000210245 likely pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.517G>C at the cDNA level. Using alternate nomenclature, this variant would be defined as BRCA2 745G>C. Located at the first nucleotide of exon 7, it disrupts a natural splice site and causes abnormal splicing. RT-PCR studies demonstrated that this variant results in skipping of exon 7 leading to a frameshift (Baert 2017). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. BRCA2 c.517G>C has been reported in individuals referred for BRCA1/2 testing (Hondow 2011, Rebbeck 2018). This variant was not observed in large population cohorts (Lek 2016). Although the nucleotide substitution results in the change of a Glycine to an Arginine at codon 173, and is called p.Gly173Arg in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. Based on currently available evidence, we consider BRCA2 c.517G>C to be a likely pathogenic variant.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000168537 SCV000219286 uncertain significance Breast and/or ovarian cancer 2017-08-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000222599 SCV000278707 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-02 criteria provided, single submitter clinical testing RNA Studies;Functionally-validated splicing mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Well-characterized mutation at same position
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258488 SCV000327159 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000257907 SCV000591691 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-19 criteria provided, single submitter clinical testing
Invitae RCV000257907 SCV000952006 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 173 of the BRCA2 protein (p.Gly173Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182177). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this variant disrupts normal BRCA2 mRNA splicing (PMID: 29280214). 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.

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