ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1225G>A (p.Glu409Lys) (rs80358416)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043761 SCV000071774 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 409 of the BRCA2 protein (p.Glu409Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs80358416, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51086). 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 lysine 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 RCV000164321 SCV000214952 likely benign Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
PreventionGenetics,PreventionGenetics RCV000679154 SCV000805649 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing
Color RCV000164321 SCV000911863 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251342 SCV001426906 uncertain significance not specified 2020-07-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1225G>A (p.Glu409Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250188 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1225G>A has been reported in the literature in one individual affected with Glioblastomas (Xiu_2016). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112895 SCV000145834 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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