ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9710G>A (p.Arg3237Lys) (rs730881575)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166335 SCV000217121 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000166335 SCV000906823 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000160178 SCV000210516 uncertain significance not provided 2014-09-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9710G>A at the cDNA level, p.Arg3237Lys (R3237K) 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 Arg3237Lys 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 Arg3237Lys occurs at a position that is variable across species 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 information, it is unclear whether BRCA2 Arg3237Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781163 SCV000919042 uncertain significance not specified 2018-12-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9710G>A (p.Arg3237Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245670 control chromosomes. 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.9710G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000530914 SCV000635756 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 3237 of the BRCA2 protein (p.Arg3237Lys). 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: 182267). 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.

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