ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6357C>G (p.Asn2119Lys) (rs1064794110)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481129 SCV000567869 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6357C>G at the cDNA level, p.Asn2119Lys (N2119K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 6585C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn2119Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Asn2119Lys occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Asn2119Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000697738 SCV000826365 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 2119 of the BRCA2 protein (p.Asn2119Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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: 419795). 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 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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