ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9455A>G (p.Glu3152Gly) (rs80359219)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214951 SCV000274583 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000114109 SCV000147639 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Counsyl RCV000114109 SCV000784963 uncertain significance Breast-ovarian cancer, familial 2 2017-02-22 criteria provided, single submitter clinical testing
GeneDx RCV000483186 SCV000567406 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9455A>G at the cDNA level, p.Glu3152Gly (E3152G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). Using alternate nomenclature, this variant would be defined as BRCA2 9683A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu3152Gly was observed at an allele frequency of 0.026% (3/11,550) in individuals of Latino ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu3152Gly occurs at a position that is conserved across species and is located within the DNA binding domain (Yang 2002). 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 Glu3152Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000779965 SCV000916930 uncertain significance not specified 2017-10-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9455A>G (p.Glu3152Gly) variant located int he BRCA2, OB3 domain (InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome. A publication, Karchin_2008 calculated the protein likelihood in favor of protein loss of function and predicted the variant to be neutral. However, these predictions have yet to be functionally assessed. This variant was found in 6/246042 control chromosomes (gnomAD), predominantly observed in the Latino subpopulation at a frequency of 0.000179 (6/33560 chrs). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000045823 SCV000073836 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 3152 of the BRCA2 protein (p.Glu3152Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs80359219, ExAC 0.03%). This variant has been reported in at least one individual from a high-risk breast/ovarian cancer family (PMID: 19043619). ClinVar contains an entry for this variant (Variation ID: 52839). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"), but an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggests that it is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on 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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