Submissions for variant NM_001040108.2(MLH3):c.1519A>G (p.Met507Val)

gnomAD frequency: 0.00001  dbSNP: rs371891794

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823663	SCV000964531	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2025-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 507 of the MLH3 protein (p.Met507Val). This variant is present in population databases (rs371891794, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 665393). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV003493745	SCV002704809	uncertain significance	not specified	2024-09-12	criteria provided, single submitter	clinical testing	The p.M507V variant (also known as c.1519A>G), located in coding exon 1 of the MLH3 gene, results from an A to G substitution at nucleotide position 1519. The methionine at codon 507 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493745	SCV004242626	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005012380	SCV005635797	uncertain significance	Endometrial carcinoma; Colorectal cancer, hereditary nonpolyposis, type 7; Colorectal cancer	2024-06-19	criteria provided, single submitter	clinical testing