ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5624A>G (p.Lys1875Arg) (rs587782583)

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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 RCV000131917 SCV000186972 uncertain significance Hereditary cancer-predisposing syndrome 2014-04-25 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 RCV000223072 SCV000279789 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5624A>G at the cDNA level, p.Lys1875Arg (K1875R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 5852A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1875Arg 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 Lys1875Arg occurs at a position that is not conserved and is not located in a known functional domain (Borg 2010). 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 Lys1875Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000688314 SCV000815920 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1875 of the BRCA2 protein (p.Lys1875Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine 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 BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142607). 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.

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