ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8972G>A (p.Arg2991His) (rs80359150)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045676 SCV000073689 benign Hereditary breast and ovarian cancer syndrome 2017-12-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131351 SCV000186326 likely benign Hereditary cancer-predisposing syndrome 2018-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Other strong data supporting benign classification
GeneDx RCV000435349 SCV000518105 likely benign not specified 2017-08-14 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.
Integrated Genetics/Laboratory Corporation of America RCV000588503 SCV000695198 likely benign not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8972G>A (p.Arg2991His) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. However, computational modeling based on Protein Likelihood Ratios predicts the variant as benign/neutral (Karchin_2008). Although computational analysis shows that this variant is predicted to cause loss of an exonic splicing enhancer (ESE) (Pettigrew_2008), in vitro minigene assay shows that this variant has no effect on splicing (Whiley_2010). This variant is found in 6/121078 control chromosomes from ExAC at a frequency of 0.0000496, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503); however, this variant could still be a rare polymorphism. This variant has been reported in multiple patients with HBOC by clinical laboratories. In one sample reported by BIC, this variant was found to co-occur with BRCA2:p.Tyr3308Ter and in another sample reported by SCRP (submission accession: SCV000054391.6), it was found to co-occur with BRCA1:3053T>G (Y978X); these multiple co-occurrence data strongly support the variant as having benign outcome. Three out of five submitters in ClinVar have classified this variant as benign/likely benign and the rest two as uncertain significance. Taken together, this variant is currently classified as Likely Benign.
Color RCV000131351 SCV000910894 likely benign Hereditary cancer-predisposing syndrome 2015-10-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031783 SCV000054391 benign Breast-ovarian cancer, familial 2 2012-01-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031783 SCV000147505 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761071 SCV000890986 uncertain significance Retinoblastoma 2016-05-11 no assertion criteria provided clinical testing

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