ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1964T>C (p.Ile655Thr)

gnomAD frequency: 0.00022  dbSNP: rs63751225
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Total submissions: 13
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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 likely benign not provided 2019-09-11 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17510385, 22703879, 8938136, 17348456, 10970186, 18383312, 16341804, 11376800, 25637381, 27600092, 31159747, 31332305)
Invitae RCV001085205 SCV000284039 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000662533 SCV000785103 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 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 Diagnostics, LLC DBA Color Health 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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001762097 SCV002009369 likely benign Muir-Torré syndrome 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000781539 SCV002070339 uncertain significance not specified 2020-08-03 criteria provided, single submitter clinical testing DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.1964T>C, in exon 17 that results in an amino acid change, p.Ile655Thr. This sequence change has been described in the gnomAD database with a low frequency of 0.016% in the European sub-population (dbSNP rs63751225). The p.Ile655Thr change affects a poorly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile655Thr substitution. The p.Ile655Thr change has previously been described in a family with gastric cancer (PMID: 8938136); however, functional studies have demonstrated mismatch repair activity similar to that of the wild type allele in the presence of this sequence change (PMID: 17510385). Due to these contrasting evidences, the clinical significance of the p.Ile655Thr change remains unknown at this time.
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000781539 SCV002550465 uncertain significance not specified 2021-11-26 no assertion criteria provided clinical testing

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