Submissions for variant NM_000249.4(MLH1):c.92C>G (p.Ala31Gly)

gnomAD frequency: 0.00003  dbSNP: rs730882127

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001149363	SCV001310309	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593923	SCV004369914	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 31 of the MLH1 protein (p.Ala31Gly). This variant is present in population databases (rs730882127, gnomAD 0.03%). 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: 183068). 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 expected to disrupt MLH1 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001149363	SCV004807214	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000161932	SCV004835233	uncertain significance	Lynch syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 31 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 22/282508 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000161932	SCV000211916	uncertain significance	Lynch syndrome	2015-02-18	no assertion criteria provided	clinical testing