ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.-426_-425delinsTG (rs63749994)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590103 SCV000149396 likely benign not provided 2020-07-20 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27150160, 20020535, 16395668, 21404117, 12624141, 28874130, 27443514, 31159747)
Ambry Genetics RCV000115487 SCV000185832 likely benign Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV001081515 SCV000218977 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000410005 SCV000487872 uncertain significance Lynch syndrome II 2015-11-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590103 SCV000601415 uncertain significance not provided 2020-05-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115487 SCV000684881 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing This missense variant replaces alanine with cysteine at codon 31 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study reported this variant protein as partially to fully impaired compared to wild-type in an in vitro DNA mismatch repair assay (PMID: 20020535). This variant has been reported in individuals with personal and/or family history of Lynch Syndrome-associated cancers (PMID: 21404117, 27443514, 28874130) and an individual affected with breast or ovarian cancer (PMID: 28828701). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235172 SCV000696189 likely benign not specified 2019-03-29 criteria provided, single submitter clinical testing Variant summary: MLH1 c.91_92delinsTG (p.Ala31Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal and Histidine kinase/HSP90-like ATPase domains of 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 7.2e-05 in 276916 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.2e-05 vs 0.00071), allowing no conclusion about variant significance. c.91_92delinsTG has been reported in the literature in individuals affected with Lynch Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3700_3704delCTAAA; CHEK2 c.1169A>C; MSH2 c.1156C>T; MLH1 c.1852_1854del), providing supporting evidence for a benign role. Functional studies show the variant to not affect splicing and to have significantly higher repair activity compared to putatively pathogenic variants, performing slightly comparable to wild type function (Auclair_2006, Drost_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, five classify as VUS while two classify as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000115487 SCV000822025 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765729 SCV000897097 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing

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