ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1964T>C (p.Ile655Thr) (rs63751225)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000128924 SCV000172794 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx RCV000034544 SCV000211118 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1964T>C at the cDNA level, p.Ile655Thr (I655T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has been identified in several individuals with colorectal cancer and a family history suspicious of Lynch syndrome, and at least one individual with gastric cancer (Keller 1996, Ravnik-Glavac 2000, Potocnik 2001, Giraldo 2005, Irmejs 2007). This variant was identified in the germline of an individual whose colon tumor showed microsatellite instability, but was also positive for MLH1 promoter hypermethylation and did not show loss of heterozygosity (Potocnik 2001). In addition, this variant was observed in one individual with atherosclerosis, with no specific information about cancer history (Johnston 2012). In vitro functional studies demonstrated this variant performs similar to wild type with regards to dominant-mutator effect, mismatch repair activity, and MLH1 expression (Takahashi 2007). MLH1 Ile655Thr was observed at an allele frequency of 0.0166% (21/126,516) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ile655Thr is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas 2011, Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Ile655Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001085205 SCV000284039 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000662533 SCV000785103 uncertain significance Lynch syndrome II 2017-04-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000128924 SCV000822021 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000128924 SCV000910738 likely benign Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781539 SCV000919656 likely benign not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1964T>C (p.Ile655Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251246 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.1964T>C has been reported in the literature in individuals affected with colorectal and other cancers and at-least one instance of co-occurrence in a patient with hMLH1 promoter hypermethylation suggestive of a sporadic etiology has been ascertained (example, Irmejs_2007, Keller_1996, Potocnik_2001, Ravnik-Glavac_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 74% of normal activity in an in-vitro MMR assay and >75% relative MLH1 expression (Takahashi_2007). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing overlapping evidence utilized in the context of this evaluation with conflicting assessments (likely benign, n=3, VUS, n=3). Based on the evidence outlined above, the variant was re-classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034544 SCV001470332 uncertain significance not provided 2019-12-29 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034544 SCV000043329 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148623 SCV000190338 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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