ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2946A>G (p.Ile982Met) (rs80358541)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081289 SCV000072104 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131646 SCV000186673 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000590161 SCV000210297 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2946A>G at the cDNA level, p.Ile982Met (I982M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). Using alternate nomenclature, this variant would be defined as BRCA2 3174A>G. This variant has been observed in at least one individual with early onset breast cancer (Lee 2008). BRCA2 Ile982Met was observed at an allele frequency of 0.06% (20/33,344) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ile982Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590161 SCV000296677 uncertain significance not provided 2019-02-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175363 SCV000694652 uncertain significance not specified 2019-10-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2946A>G (p.Ile982Met) 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 8.8e-05 in 248848 control chromosomes, predominantly at a frequency of 0.00058 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.8e-05 vs 0.00075), allowing no conclusion about variant significance. c.2946A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Lee_2008, Dong_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.141C>A, p.Cys47Ter, Dong_2018), providing supporting evidence for a benign role. 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 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (2x likely benign, 3x VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000131646 SCV000910934 likely benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Mendelics RCV000031391 SCV001139050 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031391 SCV000053996 likely benign Breast-ovarian cancer, familial 2 2014-02-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031391 SCV000146145 uncertain significance Breast-ovarian cancer, familial 2 2002-06-20 no assertion criteria provided clinical testing

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