ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2245A>G (p.Ser749Gly) (rs80358495)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043961 SCV000071974 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 749 of the BRCA2 protein (p.Ser749Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs80358495, ExAC 0.003%). This variant has been reported in an individual affected with stomach adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 51259). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000129533 SCV000184310 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000481492 SCV000564769 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2245A>G at the cDNA level, p.Ser749Gly (S749G) 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 2473A>G. This variant was observed in at least one individual with gastric cancer (Lu 2015). BRCA2 Ser749Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ser749Gly occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ser749Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113026 SCV000146020 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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