Submissions for variant NM_000249.4(MLH1):c.79C>T (p.Arg27Trp)

gnomAD frequency: 0.00001  dbSNP: rs756398627

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000570479	SCV000662063	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-26	criteria provided, single submitter	clinical testing	The p.R27W variant (also known as c.79C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 79. The arginine at codon 27 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in a cohort of 882 Chinese individuals with a personal and/or family history of breast or ovarian cancers who underwent multi-gene panel testing for HBOC risk assessment (Shao D et al. Cancer Sci, 2020 Feb;111:647-657). 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.
Color Diagnostics, LLC DBA Color Health	RCV000570479	SCV000908600	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 27 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 5/282632 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	RCV000822281	SCV000963076	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the MLH1 protein (p.Arg27Trp). This variant is present in population databases (rs756398627, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 31742824). ClinVar contains an entry for this variant (Variation ID: 479677). 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 with a positive 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317284	SCV004020508	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.79C>T (p.Arg27Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251246 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.79C>T has been reported in the literature at least once in a cohort of individuals undergoing multigene panel testing for suspected hereditary breast and ovarian cancer (HBOC). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31742824). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003459284	SCV004195077	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000839	SCV004835230	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 27 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 5/282632 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000239	SCV005623592	uncertain significance	not provided	2024-05-19	criteria provided, single submitter	clinical testing	The MLH1 c.79C>T (p.Arg27Trp) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 31742824 (2020)). The frequency of this variant in the general population, 0.00011 (4/35438 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.