ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8359C>T (p.Arg2787Cys) (rs41293517)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001088658 SCV000073504 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130122 SCV000184954 benign Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
GeneDx RCV000656804 SCV000329142 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8359C>T at the cDNA level, p.Arg2787Cys (R2787C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA2 8587C>T. This variant was identified in at least one individual undergoing clinical BRCA1/2 testing and demonstrated homology-directed repair activity comparable to wild-type in an in vitro assay (Lai 2016, Guidugli 2018). BRCA2 Arg2787Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a DSS1 contacting residue of the DNA binding domain (Yang 2002). In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. Based on currently available evidence, it is unclear whether BRCA2 Arg2787Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000305632 SCV000600798 uncertain significance not specified 2017-04-13 criteria provided, single submitter clinical testing
Counsyl RCV000113912 SCV000785084 uncertain significance Breast-ovarian cancer, familial 2 2017-04-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130122 SCV000903960 likely benign Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000305632 SCV001363149 uncertain significance not specified 2019-05-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8359C>T (p.Arg2787Cys) results in a non-conservative amino acid change located in the OB1 (oligonucleotide binding) fold (IPR015187) of the DNA-binding domain of the BRCA2 protein. Three 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 251422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8359C>T in individuals affected with Hereditary Breast and Ovarian Cancer has been published. At least one publication reports experimental evidence evaluating an impact on protein function (Guidugli_2018). These results showed no damaging effect for this variant. In addition, co-occurrences with other pathogenic variants have been reported (BRCA1 c.4612C>T (p.Gln1538Ter) and BRCA2 c.1414C>T (p.Gln472Ter) in the BIC database), providing supporting evidence for a benign role. 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; two calling it likely benign and three classifying it as a VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113912 SCV000147333 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
King Laboratory,University of Washington RCV000305632 SCV001251303 benign not specified 2019-09-01 no assertion criteria provided research
Center of Medical Genetics and Primary Health Care RCV001269500 SCV001449142 likely benign Malignant tumor of breast no assertion criteria provided clinical testing

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