ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1564G>C (p.Gly522Arg) (rs80358442)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043829 SCV000071842 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-07-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 522 of the BRCA2 protein (p.Gly522Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs80358442, ExAC 0.009%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22476429, 24916970). ClinVar contains an entry for this variant (Variation ID: 37746). 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, 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.
GeneDx RCV000200975 SCV000210273 likely benign not specified 2017-12-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000165147 SCV000215858 likely benign Hereditary cancer-predisposing syndrome 2019-02-09 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200975 SCV000694545 likely benign not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1564G>C (p.Gly522Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 239116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1564G>C has been reported in the literature in a proband from high-risk breast and/or ovarian cancer family that did not carry BRCA1 or BRCA2 mutations (Lu_2012), among variants of unknown significance in a Portuguese breast/ovarian cancer family (Peixoto_2014), and among secondary variants identified in a study of Individuals undergoing Exome Sequencing (Johnston_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported [BRCA1 c.5136G>A, p.Trp1712Ter (BIC database); BRCA1 c.4258C>T, p.Gln1420Ter (UMD database)], providing supporting evidence for a benign role. No conclusive experimental evidence reporting an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2, VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. We have not identified any concrete evidence supporting a deleterious outcome in reports spanning over 6 years of assessment. Based on the evidence outlined above, the variant was re-classified as likely benign.
Counsyl RCV000031327 SCV000785157 uncertain significance Breast-ovarian cancer, familial 2 2017-05-16 criteria provided, single submitter clinical testing
Mendelics RCV000043829 SCV000838761 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165147 SCV000902872 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Mendelics RCV000031327 SCV001139004 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034431 SCV000043198 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031327 SCV000053932 uncertain significance Breast-ovarian cancer, familial 2 2010-10-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031327 SCV000145889 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353896 SCV000591753 uncertain significance Endometrial carcinoma no assertion criteria provided clinical testing The p.Gly522Arg variant was not identified in the literature but has been reported in the dbSNP (rs80358442), Exome Server Project, UMD (1x as an unknown variant) and BIC (7x with unknown clinical importance) databases. This residue is not conserved in mammals, increasing the likelihood this variant may not have clinical significance. Computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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