ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3299C>T (p.Thr1100Met) (rs63750442)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000074836 SCV000212177 uncertain significance Lynch syndrome 2015-03-11 criteria provided, single submitter research
Invitae RCV000524169 SCV000254313 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1100 of the MSH6 protein (p.Thr1100Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs63750442, ExAC 0.01%). This variant has been reported in individuals affected with colorectal cancer or other Lynch syndrome-associated cancer (PMID: 11709755, 26901136, 25980754). It has also been observed in an individual affected with colon cancer (Invitae). However, in that individual a pathogenic allele was also identified in PMS2, which suggests that this c.3299C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89369). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 26333163). The methionine 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. 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 RCV000622259 SCV000274229 uncertain significance Inborn genetic diseases 2016-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
GeneDx RCV000587747 SCV000279107 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3299C>T at the cDNA level, p.Thr1100Met (T1100M) 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 two individuals with early-onset colorectal cancer; tumor studies on one case revealed low microsatellite instability (MSI-L) and presence of MSH6, MLH1, and MSH2 proteins on immunohistochemistry (IHC) (Berends 2002, de Voer 2016). In addition, MSH6 Thr1100Met was documented in an individual with suspected Lynch syndrome and/or polyps (Yurgelun 2015). MSH6 Thr1100Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (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 Thr1100Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000218926 SCV000685385 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587747 SCV000695856 uncertain significance not provided 2016-10-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3299C>T (p.Thr1100Met) variant located in the DNA mismatch repair protein MutS, core domain (via InterPro) causes a missense change involving a conserved nucleotide with 3/5 in silico tools predict a damaging 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 6/121370 (1/20242), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. The variant of interest has been reported in affected individuals via publications. Multiple clinical diagnostic laboratories/databases cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000223174 SCV000731376 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing The p.Thr1100Met variant in MSH6 has been reported in 2 individuals with suspect ed colorectal cancer or Lynch syndrome (Berends 2002, Yurgelun 2015). This varia nt has also been identified in 2/16512 of South Asian chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750442). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In addition, the p.Thr1100Met va riant has been classified as a variant of uncertain significance on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108047.2). In summ ary, the clinical significance of the p.Thr1100Met variant is uncertain.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625242 SCV000744297 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764431 SCV000895488 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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