ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3437A>G (p.Glu1146Gly) (rs80358588)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044192 SCV000072205 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1146 of the BRCA2 protein (p.Glu1146Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs80358588, ExAC 0.002%). This variant has been reported in an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 37840). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000129732 SCV000184537 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneKor MSA RCV000129732 SCV000821933 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000129732 SCV000906898 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780046 SCV000917063 uncertain significance not specified 2018-12-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3437A>G (p.Glu1146Gly) 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 4.1e-06 in 245824 control chromosomes (gnomAD). 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.3437A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three 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.
Sharing Clinical Reports Project (SCRP) RCV000031421 SCV000054026 uncertain significance Breast-ovarian cancer, familial 2 2011-05-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031421 SCV000146233 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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