ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8573A>G (p.Gln2858Arg) (rs80359114)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045562 SCV000073575 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131683 SCV000186719 likely benign Hereditary cancer-predisposing syndrome 2019-03-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000656806 SCV000210478 uncertain significance not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8573A>G at the cDNA level, p.Gln2858Arg (Q2858R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant, also known as BRCA2 8801A>G using alternate nomenclature, was observed in 2 families with multiple cases of breast and/or ovarian cancer and has been reported in combination with a pathogenic BRCA1 variant, Glu352Ter (Simard 2007, Spurdle 2008). This variant was also observed in an individual with oropharyngeal cancer diagnosed before age 50 (Chandrasekharappa 2017). In a large case-control analysis, BRCA2 Gln2858Arg was not significantly associated with breast cancer (Shimelis 2017). In addition, this variant was predicted to be likely not pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants (Spurdle 2008, Lindor 2012). BRCA2 Gln2858Arg was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). 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 Gln2858Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656806 SCV000227605 uncertain significance not provided 2015-01-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656806 SCV000296596 uncertain significance not provided 2019-01-19 criteria provided, single submitter clinical testing
Counsyl RCV000113963 SCV000785686 likely benign Breast-ovarian cancer, familial 2 2017-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131683 SCV000902975 likely benign Hereditary cancer-predisposing syndrome 2015-12-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192535 SCV001360746 benign not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8573A>G (p.Gln2858Arg) results in a conservative amino acid change located in the Tower domain (IPR015205) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251234 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8573A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Simard_2007, Spurdle_2008, Shimelis_2017). These data do not allow any conclusion about variant significance. Co-occurrences with pathogenic variants have been reported in the BIC database (BRCA1 c.1054G>T, p.Glu352X; BRCA1 c.2035A>T, p.Lys679X), providing supporting evidence for a benign role. In addition, a multifactorial probability based model utilized for performing systematic assessment of variants of unknown significance in the BRCA genes, which includes 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, predicts this variant to be likely not pathogenic or of little clinical significance (Lindor_2012). One publication, Hart_2018, reports the HDR activity of this variant to be similar to that of wild-type and classifies the variant as neutral. Seven ClinVar submitters (evaluation after 2014) cite this variant as likely benign (n=4) and as uncertain significance (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of evidence supporting an actionable outcome as outlined above, the variant was classified as benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113963 SCV000147404 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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