ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7874G>A (p.Arg2625Lys) (rs864622552)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204378 SCV000261095 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-10-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2625 of the BRCA2 protein (p.Arg2625Lys). The arginine residue is highly 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483772 SCV000569381 uncertain significance not provided 2016-02-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7874G>A at the cDNA level, p.Arg2625Lys (R2625K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 8102G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Arg2625Lys 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 Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Arg2625Lys occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in DNA binding domain as well as in a region reported to interact with SHFM1 (Marston 1999, Yang 2002) . In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Arg2625Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509944 SCV000608025 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000779999 SCV000916987 uncertain significance not specified 2018-08-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7874G>A (p.Arg2625Lys) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246032 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7874G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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