ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2003G>A (p.Arg668Lys) (rs80358483)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043934 SCV000071947 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 668 of the BRCA2 protein (p.Arg668Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. 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. ClinVar contains an entry for this variant (Variation ID: 51235). 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 rare 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.
GeneDx RCV000212217 SCV000210280 uncertain significance not provided 2014-05-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2003G>A at the cDNA level, p.Arg668Lys (R668K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg668Lys 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 Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg668Lys occurs at a position that is moderately conserved through mammals, but not in other species, and is located in region that interacts with Nucleophosmin 1. In addition, 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 Arg668Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113004 SCV000145990 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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