Submissions for variant NM_000249.4(MLH1):c.786C>G (p.Ile262Met)

gnomAD frequency: 0.00001  dbSNP: rs748553134

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167152	SCV000217982	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	The p.I262M variant (also known as c.786C>G), located in coding exon 9 of the MLH1 gene, results from a C to G substitution at nucleotide position 786. The isoleucine at codon 262 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000205244	SCV000261355	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 262 of the MLH1 protein (p.Ile262Met). This variant is present in population databases (rs748553134, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187425). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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	RCV000479410	SCV000569904	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.786C>G at the cDNA level, p.Ile262Met (I262M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATC>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ile262Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ile262Met occurs at a position that is conserved across species and is not located in a known functional domain (Raevaara 2005, UniProt). 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 Ile262Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000167152	SCV000684866	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 262 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/250438 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000651	SCV001157677	uncertain significance	not specified	2018-08-11	criteria provided, single submitter	clinical testing	The MLH1 c.786C>G; p.Ile262Met variant (rs748553134), to our knowledge, is not reported in the medical literature, but is reported by multiple laboratories in ClinVar (Variation ID: 187425). This variant is found in the general population with a low overall allele frequency of 0.0004% (1/245334 alleles) in the Genome Aggregation Database. The isoleucine at codon 262 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Ile262Met variant is uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV003995564	SCV004840906	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 262 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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 1/250438 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.