ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5945G>C (p.Ser1982Thr) (rs28897738)

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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 RCV000510094 SCV000607808 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000113507 SCV000146735 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000510094 SCV000688958 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000590082 SCV000210376 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5945G>C at the cDNA level, p.Ser1982Thr (S1982T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 6173G>C. This variant has been observed several times in cis with a known pathogenic BRCA2 variant (Chenevix-Trench 2006) and was observed in at least one individual with familial breast cancer (Morgan 2010). BRCA2 Ser1982Thr was not observed in large population cohorts (Lek 2016). This variant is located in the BRC7 domain and RAD51 binding domain (Cole 2011, Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, it is unclear whether BRCA2 Ser1982Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590082 SCV000694918 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The c.5945G>C variant affects a conserved nucleotide, resulting in amino acid change from Ser to Thr. 4/5 in-silico tools predict this variant to be damaging. This variant is absent in 120698 control chromosomes. Multiple clinical laboratories and reputable databases classified this variant as VUS. However, this variant has been reported in multiple patients with BRCA2 c.4163_4164delCTinsA/p.Thr1388Asnfs in cis by BIC and kConFab, suggesting variant of interest is benign. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000203657 SCV000072809 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1982 of the BRCA2 protein (p.Ser1982Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual at risk for hereditary breast and ovarian cancer (PMID: 20127978). ClinVar contains an entry for this variant (Variation ID: 38010). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044796 SCV000600671 uncertain significance not specified 2016-11-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590082 SCV000889084 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing

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