Submissions for variant NM_000249.4(MLH1):c.1572G>T (p.Met524Ile)

dbSNP: rs587779953

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167029	SCV000217852	likely benign	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000459950	SCV000543582	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 524 of the MLH1 protein (p.Met524Ile). This variant is present in population databases (rs587779953, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 187310). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000521886	SCV000617046	uncertain significance	not provided	2017-12-18	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1572G>T at the cDNA level, p.Met524Ile (M524I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATT). This germline variant was observed once in a series of 1893 epithelial ovarian cancer cases (Pal 2012). MLH1 Met524Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Met524Ile is located in the region of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Met524Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000167029	SCV000684756	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 524 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549). In a pancreatic case-control study, the variant was reported in 1/1005 pancreatic cancer cases and 67/23705 controls (PMID: 32980694). This variant has been identified in 1/251158 chromosomes 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.
Counsyl	RCV000663082	SCV000786165	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-03-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764494	SCV000895565	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663082	SCV004043194	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987389	SCV004804365	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1572G>T (p.Met524Ile) results in a conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (IPR032189) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1572G>T has been reported in the literature in an individual affected with Ovarian Cancer without strong evidence of causality (Pal_2012). This report does not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 23047549). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995549	SCV004841045	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 524 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) or pancreatic cancer (PMID: 32980694). However, this variant has also been reported in multiple healthy individuals (PMID: 32980694). This variant has been identified in 1/251158 chromosomes 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.