ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5518G>C (p.Gly1840Arg) (rs398122533)

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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 RCV000510044 SCV000608237 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000510044 SCV000688930 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000478840 SCV000567396 uncertain significance not provided 2015-07-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5518G>C at the cDNA level, p.Gly1840Arg (G1840R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). Using alternate nomenclature, this variant would be defined as BRCA2 5746G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Gly1840Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly1840Arg occurs at a position that is not conserved and is located in the BRC repeat region and region of interaction with RAD51 (Narod 2004, Roy 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Gly1840Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000464863 SCV000549708 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-03-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1840 of the BRCA2 protein (p.Gly1840Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. 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: 91416). 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.
Sharing Clinical Reports Project (SCRP) RCV000076933 SCV000108730 uncertain significance Breast-ovarian cancer, familial 2 2009-12-07 no assertion criteria provided clinical testing

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