ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8764A>G (p.Ser2922Gly) (rs80359132)

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Total submissions: 11
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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) RCV000031769 SCV001161625 benign Breast-ovarian cancer, familial 2 2019-06-18 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 = 0.000712
Invitae RCV000195383 SCV000073636 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000590809 SCV000210482 uncertain significance not provided 2018-12-26 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8764A>G at the cDNA level, p.Ser2922Gly (S2922G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8992A>G. This variant has been observed in at least one individual with a history of early-onset breast cancer (Foley 2015). BRCA2 Ser2922Gly was not observed at a significant allele 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 Ser2922Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165036 SCV000215734 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045623 SCV000592229 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing
Color RCV000165036 SCV000683997 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590809 SCV000695182 likely benign not provided 2016-04-15 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/119794, which does not exceed the predicted maximal expected allele frequency of a pathogenic BRCA2 variant of 1/1333. The variant of interest has been reported in an affected individual via publication(s), although with limited information (ie lack of co-occurrence, co-segregation data). Our laboratory received a Myriad report for a patient, in which Myriad reports the variant of interest to co-occur with a pathogenic BRCA2 variant, c.4480_4483delAGTG (legacy name: 4708del4, p.Val1495fsX8 - scored as pathogenic by Myriad)(Internal LCA data), indicating the missense variant of interest to be in the benign spectrum. Additionally, BIC cites the variant to co-occur with a pathogenic BRCA2 variant, c.4478_4481delAAAG (p.Glu1493fs - classified as pathogenic by LCA). Multiple reputable databases/clinical laboratories cite the variant with conflicting classifications "uncertain signifcance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as likely benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590809 SCV001133948 uncertain significance not provided 2019-04-25 criteria provided, single submitter clinical testing
Mendelics RCV000031769 SCV001139233 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031769 SCV000054377 likely benign Breast-ovarian cancer, familial 2 2009-03-26 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031769 SCV000147457 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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