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

dbSNP: rs587779953

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115462	SCV000149371	uncertain significance	not provided	2013-10-08	criteria provided, single submitter	clinical testing	This variant in exon 14 of the MLH1 gene is denoted c.1572G>C at the cDNA level and p.Met524Ile (M524I) at the protein level. The M524I variant has not been published as a mutation nor has it been reported as a benign polymorphism, to our knowledge. The NHLBI ESP Exome Variant Server reports M524I was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. This amino acid substitution results in the conservative replacement of a neutral, non-polar Methionine residue (ATG) with a neutral, non-polar Isoleucine residue (ATC) at a position that is conserved throughout evolution. The M524I variant is located in a domain of MLH1 that interacts with exonuclease 1; and multiple in silico algorithms predict that this variant may be benign. Previously reported mutations in nearby codons are predominantly nonsense changes. Based on the currently available information, it is unclear whether M524I is a pathogenic mutation or a rare benign variant.The variant is found in BR-OV-HEREDIC panel(s).
Ambry Genetics	RCV001012209	SCV001172635	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.M524I variant (also known as c.1572G>C), located in coding exon 14 of the MLH1 gene, results from a G to C substitution at nucleotide position 1572. The methionine at codon 524 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected once in a cohort of 1893 women with epithelial ovarian cancer from three population-based studies who were ascertained for mutations in MLH1, MSH2 and MSH6 (Pal T et al. Br J Cancer, 2012 Nov;107:1783-90). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030629	SCV001193611	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058475	SCV001223049	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001149457	SCV001310409	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001012209	SCV001351186	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192573	SCV001360800	uncertain significance	not specified	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1572G>C (p.Met524Ile) results in a conservative amino acid change located in the C-terminal domain (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>C has been reported in the literature as somatic occurrences (Kobayashi_2019 and Sakai_2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (APC c.3184_3187delCAAA, p.Gln1062ValfsX63). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001149457	SCV004190613	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358366	SCV001554078	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Met524Ile variant was not identified in the literature nor was it identified in the Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs587779953) as “With Uncertain significance allele,” ClinVar (as uncertain significance by GeneDx, Ambry Genetics, and Invitae), and Clinvitae (as uncertain significance). The variant was identified in control databases in 1 of 245896 chromosomes at a frequency of 0.000004 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Met524Ile residue is not conserved in mammals and the variant amino acid Isoleucine (Ile) is present in mice, increasing the likelihood that this variant does not have clinical significance. In addition, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.