Submissions for variant NM_000249.4(MLH1):c.28C>G (p.Arg10Gly)

dbSNP: rs1193754562

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506936	SCV000601393	uncertain significance	not specified	2017-02-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580223	SCV000684810	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 10 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 1/251438 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.
Ambry Genetics	RCV000580223	SCV001177915	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-17	criteria provided, single submitter	clinical testing	The p.R10G variant (also known as c.28C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 28. The arginine at codon 10 is replaced by glycine, an amino acid with dissimilar 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	RCV001045560	SCV001209420	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 10 of the MLH1 protein (p.Arg10Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 439176). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV004003542	SCV004835212	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 10 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 hereditary cancer in the literature. This variant has been identified in 1/251438 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.