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 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.91_92delGCinsTG at the cDNA level and p.Ala31Cys (A31C) at the protein level. The normal sequence, with the bases that are altered in brackets, is TAAT[delGC][insTG]TATC. This in-frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of an Alanine to a Cysteine (GCT>TGT). This variant has been observed in individuals from families meeting either the Amsterdam II Criteria and/or Bethesda guidelines for Lynch syndrome (Hardt 2011, Rossi 2017). One of these individuals was diagnosed with early onset rectal cancer exhibiting microsatellite stability and normal expression of the MLH1 and PMS2 proteins (Hardt 2011). This variant was also observed in an individual with endometrial cancer (Ring 2016). An in vitro complementation assay found that MLH1 Ala31Cys demonstrated a level of mismatch repair activity that was significantly higher than that observed in established pathogenic variants, but lower than the activity level seen in a wild-type control and established benign variants (Drost 2010). Neither MLH1 c.91_92delGCinsTG nor MLH1 Ala31Cys (by this or an alternate nucleotide change) was not observed in large population cohorts (Lek 2016). Since Alanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ala31Cys occurs at a position that is conserved across species and is located within the ATP binding and hydrolysis domain (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala31Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-30 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 RCV000235172 SCV000601415 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing
Color RCV000115487 SCV000684881 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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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