ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1270G>C (p.Gly424Arg) (rs763051683)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482955 SCV000566407 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1270G>C at the cDNA level, p.Gly424Arg (G424R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). Using alternate nomenclature, this variant would be defined as BRCA1 1389G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly424Arg was not observed in large population cohorts (Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly424Arg occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). Protein based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, while splicing models predict that this variant may strengthen the cryptic splice acceptor site and possibly cause abnormal splicing. Based on currently available evidence, it is unclear whether BRCA1 Gly424Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561054 SCV000660985 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000690584 SCV000818274 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 424 of the BRCA1 protein (p.Gly424Arg). The glycine residue is moderately 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 418958). 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: "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.

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