ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5737T>G (p.Cys1913Gly) (rs80358799)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130867 SCV000185767 likely benign Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000082948 SCV000146684 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000130867 SCV000903518 likely benign Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing
Counsyl RCV000082948 SCV000785891 uncertain significance Breast-ovarian cancer, familial 2 2018-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000588195 SCV000279232 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5737T>G at the cDNA level, p.Cys1913Gly (C1913G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 5965T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Cys1913Gly was not observed at a significant frequency in large population cohorts (Lek 2016). Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Cys1913Gly is located in the RAD51 binding domain (Roy 2012). In-silico analyses, including protein predictors, splice predictors, and evolutionary conservation, support a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Cys1913Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588195 SCV000694897 uncertain significance not provided 2016-08-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5737T>G (p.Cys1913Gly) variant involves the alteration of a non-conserved nucleotide and results in a replacement of a medium size and polar Cysteine (C) with a small size and hydrophobic Glycine (G). 3/5 in silico tools predict a benign outcome for this substitution. This variant is absent in 120994 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS or likely benign. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000257905 SCV000549884 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 1913 of the BRCA2 protein (p.Cys1913Gly). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 96827). 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 and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000168581 SCV000600661 uncertain significance not specified 2016-07-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082948 SCV000115022 likely benign Breast-ovarian cancer, familial 2 2013-12-06 no assertion criteria provided clinical testing

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