ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9509A>G (p.Asp3170Gly) (rs80359224)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000114127 SCV000244494 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000264
Ambry Genetics RCV000163018 SCV000213506 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000440286 SCV000522107 likely benign not specified 2015-12-12 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000440286 SCV000600865 benign not specified 2016-03-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000440286 SCV000602759 benign not specified 2016-08-06 criteria provided, single submitter clinical testing
Color RCV000163018 SCV000689205 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000440286 SCV000695249 likely benign not specified 2019-04-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9509A>G (p.Asp3170Gly) results in a non-conservative amino acid change located in the BRCA2, OB3 domain 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 251308 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). Karchin_2008 classified variant as neutral based on protein likelihood ratio classification. Guidugli_2013 also listed variant as neutral variant. To our knowledge, no occurrence of c.9509A>G in families affected with Hereditary Breast and Ovarian Cancer has been reported. Two publications indicated the functional impact of this variant by HDR assay. One reported this variant effect results in >50%-90% of normal activity and the other one results in >90% of normal activity. Five submitters including and one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters including the expert panel have classified the variant as benign (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign until additional clinical and functional evidence become available.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770737 SCV000902220 likely benign Breast and/or ovarian cancer 2016-12-21 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000114127 SCV000147660 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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