Submissions for variant NM_000249.4(MLH1):c.769A>G (p.Ile257Val)

dbSNP: rs876660094

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219365	SCV000277229	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-17	criteria provided, single submitter	clinical testing	The p.I257V variant (also known as c.769A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 769. The isoleucine at codon 257 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is not 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 p.I257V remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813096	SCV000953434	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 257 of the MLH1 protein (p.Ile257Val). This variant is not present in population databases (gnomAD no frequency). 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: 232951). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
All of Us Research Program, National Institutes of Health	RCV003998014	SCV004839065	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 257 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 MLH1-related disorders in the literature. This variant has been identified in 1/251042 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.