ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2915A>G (p.Lys972Arg) (rs1064794885)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564626 SCV000668630 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000483494 SCV000570154 uncertain significance not provided 2016-04-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2915A>G at the cDNA level, p.Lys972Arg (K972R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 3143A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys972Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys972Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys972Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000528453 SCV000635258 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-05-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 972 of the BRCA2 protein (p.Lys972Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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