ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3137A>G (p.Glu1046Gly) (rs80358559)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044123 SCV000072136 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1046 of the BRCA2 protein (p.Glu1046Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 16284991). ClinVar contains an entry for this variant (Variation ID: 51403). 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: "Probably 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.
Ambry Genetics RCV000129709 SCV000184510 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000483875 SCV000567200 uncertain significance not provided 2016-10-31 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3137A>G at the cDNA level, p.Glu1046Gly (E1046G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). This variant, also known as BRCA2 3365A>G using alternate nomenclature, has been observed in at least one woman with a history of ovarian cancer (Pal 2005). BRCA2 Glu1046Gly 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 Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu1046Gly occurs at a position that is not conserved and is located in RAD51 binding domain (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 Glu1046Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000113138 SCV000785029 uncertain significance Breast-ovarian cancer, familial 2 2017-03-16 criteria provided, single submitter clinical testing
Color RCV000129709 SCV000911039 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779942 SCV000916884 uncertain significance not specified 2019-07-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3137A>G (p.Glu1046Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246562 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3137A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Pal_2005) and glioma (Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113138 SCV000146176 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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