ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9271G>A (p.Val3091Ile) (rs80359194)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167774 SCV000073785 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-30 criteria provided, single submitter clinical testing
GeneDx RCV000045772 SCV000210685 likely benign not specified 2017-07-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000165867 SCV000216616 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Counsyl RCV000083157 SCV000489188 uncertain significance Breast-ovarian cancer, familial 2 2016-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045772 SCV000695230 uncertain significance not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9271G>A (p.Val3091Ile) results in a conservative amino acid change located in the OB3 fold (IPR015188) of 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 4e-06 in 250418 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9271G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, gastric adenocarcinoma and pancreatic cancer (Balia_2011, Kwong_2012, Schenkel_2016, Chen_2015, Peixoto_2014, Dudley_2018, Santonocito_2020), however it was also found in controls (Momozawa_2018, Ko_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Two functional studies from the same group utilizing homologous recombination assays to evaluate an impact on protein function, provided conflicting results about the variant (Spugnesi_2013, Balia_2011). However, a more recent study utilizing a cell-based homology directed DNA repair activity assay, with an estimated high sensitivity and specificity, determined the variant to be neutral (i.e. not deleterious) (Hart_2019). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (i.e. 3 calling it VUS, 3 as likely benign, and 1 as benign). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Health, Inc RCV000165867 SCV000911042 benign Hereditary cancer-predisposing syndrome 2017-01-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985621 SCV001133972 uncertain significance not provided 2020-04-10 criteria provided, single submitter clinical testing
Mendelics RCV000083157 SCV001139254 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083157 SCV000115231 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083157 SCV000147595 uncertain significance Breast-ovarian cancer, familial 2 2002-12-23 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045772 SCV000587994 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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