ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3425C>T (p.Thr1142Met) (rs267608089)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656899 SCV000149324 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3425C>T at the cDNA level, p.Thr1142Met (T1142M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been observed in at least one individual undergoing hereditary cancer panel testing due to a personal and/or family history of breast and/or ovarian cancer (Cast?ra 2014). While P?rez-Cabornero et al. (2013) reported this variant as ?probably pathogenic? based on in silico models, absence in 347 Spanish cancer-free controls, and co-segregation with colon polyps in one small family, the authors also noted that the effect of this variant on protein function is unknown. On functional interrogation, Houlleberghs et al. (2017) did not find that MSH6 Thr1142Met confers resistance to thiopurine 6-thioguanine (6TG), suggesting intact mismatch repair activity. Additionally, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as ?uncertain? based on insufficient evidence (Thompson 2014). MSH6 Thr1142Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain and within an ATP binding motif (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr1142Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524175 SCV000166230 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1142 of the MSH6 protein (p.Thr1142Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs267608089, ExAC 0.006%). This variant has been reported in a family affected with Lynch syndrome (PMID: 23523604, 19250818), and an individual with a personal and/or family history of breast/ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 89381). An algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be deleterious. However, this prediction has 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 RCV000115415 SCV000186590 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212683 SCV000539707 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 VUS (including expert panel - no new evidence since expert classification)
Color RCV000115415 SCV000685399 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656899 SCV000888273 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing

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