ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.359T>C (p.Ile120Thr) (rs775971872)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214442 SCV000273040 likely benign Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Color RCV000214442 SCV000911036 likely benign Hereditary cancer-predisposing syndrome 2016-09-27 criteria provided, single submitter clinical testing
GeneDx RCV000589961 SCV000279267 uncertain significance not provided 2015-10-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.359T>C at the cDNA level, p.Ile120Thr (I120T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant was observed in at least one family meeting Amsterdam criteria with colon tumor analysis showing high microsatellite instability as well as loss of MLH1 protein expression (Wielandt 2012). MSH6 Ile120Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ile120Thr occurs at a position that is not conserved and is located in the PWWP domain (UniProt, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ile120Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589961 SCV000695877 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/5 in silico programs predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121410 (1/60705), all in the Latino cohort, 2/11578 (1/5789), which does not significantly exceed the predicted maximum expected allele frequency for a pathogenic MSH6 variant of 1/7037. The variant of interest has been reported in affected individuals via publications, although with limited information, although one pt was indicated to have the expression of MLH1 to be absent. However, no reputable databases or clinical laboratories have cited the variant of interest. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000629813 SCV000750769 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 120 of the MSH6 protein (p.Ile120Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs775971872, ExAC 0.02%). This variant has been reported in a family affected with Lynch syndrome (PMID: 23354634). ClinVar contains an entry for this variant (Variation ID: 229725). 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: "Possibly 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.
Mendelics RCV000708853 SCV000837865 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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