ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1106C>T (p.Thr369Ile) (rs375974046)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212645 SCV000149277 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1106C>T at the cDNA level, p.Thr369Ile (T369I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has been observed in an individual with ovarian cancer and colon polyps and in an individual with microsatellite-stable endometrial cancer (Price 2014, Shirts 2016). MSH6 Thr369Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Thr369Ile is located in the mismatch binding domain and the nuclear localization signal (Warren 2007, Gassman 2011, 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 Thr369Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115368 SCV000216876 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000210148 SCV000266199 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000528613 SCV000624612 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 369 of the MSH6 protein (p.Thr369Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs375974046, ExAC 0.006%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 127554). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000662663 SCV000785352 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-07-11 criteria provided, single submitter clinical testing
Color RCV000115368 SCV001344147 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193101 SCV001361709 uncertain significance not specified 2019-03-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1106C>T (p.Thr369Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245742 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in one individual affected with ovarian cancer (Shirts_2016). The report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415687 SCV000493756 uncertain significance Lynch syndrome I 2015-12-04 no assertion criteria provided clinical testing

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