Submissions for variant NM_000249.4(MLH1):c.43G>A (p.Val15Met)

dbSNP: rs876660301

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221816	SCV000277616	likely benign	Hereditary cancer-predisposing syndrome	2020-12-16	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.
GeneDx	RCV000479027	SCV000567668	uncertain significance	not provided	2017-02-22	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.43G>A at the cDNA level, p.Val15Met (V15M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Val15Met 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 Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val15Met occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Val15Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000527289	SCV000625163	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-20	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (Invitae). 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. 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 233273). This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in MLH1 in at least one individual (Invitae), which suggests that this variant may not be disease-causing. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 15 of the MLH1 protein (p.Val15Met).
All of Us Research Program, National Institutes of Health	RCV003998042	SCV004824599	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 15 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 been reported in an individual affected with MLH1-related conditions who also carried a pathogenic variant in the MLH1 gene in trans that could explain the observed phenotype (ClinVar SCV000625163.4). This variant has not been identified 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.