ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165036 SCV000215734 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031769 SCV000147457 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000165036 SCV000683997 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045623 SCV000592229 uncertain significance not specified 2016-10-13 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.
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.
Invitae RCV000195383 SCV000073636 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 2922 of the BRCA2 protein (p.Ser2922Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs80359132, ExAC 0.01%). This variant has been reported in the literature in an individual with breast cancer and in individuals in the Breast Cancer Information Core database (PMID: 2602368, 10923033). However, in one of those individuals a pathogenic allele was identified in the BRCA2 gene, which suggests that this c.8764A>G substitution in BRCA2 was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 38186). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031769 SCV000054377 likely benign Breast-ovarian cancer, familial 2 2009-03-26 no assertion criteria provided clinical testing

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