ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.766G>A (p.Ala256Thr) (rs377403073)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160627 SCV000211226 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.766G>A at the cDNA level, p.Ala256Thr (A256T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has been observed in an individual with epithelial ovarian cancer (Pal 2012). MSH2 Ala256Thr was observed at an allele frequency of 0.06% (14/24014) in individuals of African ancestry in large population cohorts (Lek 2016). MSH2 Ala256Thr is located in the connector domain (Lutzen 2008, Kansikas 2011). 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 MSH2 Ala256Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196535 SCV000254429 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 256 of the MSH2 protein (p.Ala256Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs377403073, ExAC 0.06%). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 182590). 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: "Benign"; 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.
Ambry Genetics RCV000491536 SCV000580572 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000662661 SCV000785350 uncertain significance Lynch syndrome I 2017-07-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160627 SCV000888231 uncertain significance not provided 2019-01-30 criteria provided, single submitter clinical testing
Color RCV000491536 SCV000911380 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing

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