Submissions for variant NM_000249.4(MLH1):c.2029A>T (p.Ser677Cys)

dbSNP: rs587780681

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122973	SCV000166248	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 677 of the MLH1 protein (p.Ser677Cys). This variant is present in population databases (rs587780681, gnomAD 0.002%). 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: 135849). 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 not expected to disrupt MLH1 protein function with a negative 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.
GeneDx	RCV000486466	SCV000569265	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2029A>T at the cDNA level, p.Ser677Cys (S677C) at the protein level, and results in the change of a Serine to a Cysteine (AGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser677Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser677Cys occurs at a position that is conserved across species and is located within the region required for interaction with PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). 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 Ser677Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001014133	SCV001174809	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-01	criteria provided, single submitter	clinical testing	The p.S677C variant (also known as c.2029A>T), located in coding exon 18 of the MLH1 gene, results from an A to T substitution at nucleotide position 2029. The serine at codon 677 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is well 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	RCV001014133	SCV001346831	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cystine at codon 677 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/282670 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.
Sema4, Sema4	RCV001014133	SCV002528703	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	curation
Baylor Genetics	RCV003474737	SCV004195024	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997402	SCV004843254	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cystine at codon 677 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 2/282670 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	RCV000486466	SCV005623568	uncertain significance	not provided	2024-03-18	criteria provided, single submitter	clinical testing	The MLH1 c.2029A>T (p.Ser677Cys) variant has not been reported in individuals with MLH1-related conditions in the published literature. The frequency of this variant in the general population, 0.0000071 (2/282670 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.