Submissions for variant NM_000249.4(MLH1):c.301G>A (p.Gly101Ser)

dbSNP: rs267607726

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075623	SCV000106625	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
GeneDx	RCV000486320	SCV000565140	likely pathogenic	not provided	2016-12-23	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.301G>A at the cDNA level, p.Gly101Ser (G101S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been reported in individuals with a personal history of colorectal cancer and/or Lynch syndrome (Parc 2003, Tournier 2008, De Lellis 2013, Tricarico 2016). One of these individuals who met Amsterdam criteria, and whose tumor was microsatellite high and demonstrated loss of MLH1 on mismatch repair immunohistochemistry (De Lellis 2013). Despite MLH1 and PMS2 protein expression levels similar to wild-type, in vitro functional assays demonstrate MLH1 Gly101Ser to have a significant loss of mismatch repair activity supporting a deleterious effect (Tricarico 2016).MLH1 Gly101Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly101Ser occurs at a position that is conserved across species and is located within the ATPase and MLH domains and in ATP-binding and hydrolysis motif (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider MLH1 Gly101Ser to be a likely pathogenic variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502831	SCV000592346	uncertain significance	not specified	2014-12-05	criteria provided, single submitter	clinical testing
Invitae	RCV001211883	SCV001383446	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 101 of the MLH1 protein (p.Gly101Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141, 18561205, 24278394, 27629256). ClinVar contains an entry for this variant (Variation ID: 90137). 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 27629256, 30504929). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV003162483	SCV003882783	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-02	criteria provided, single submitter	clinical testing	The p.G101S variant (also known as c.301G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 301. The glycine at codon 101 is replaced by serine, an amino acid with similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1 expression by immunohistochemistry (Ambry internal data; De Lellis L et al. PLoS One, 2013 Nov;8:e81194). Additional studies have reported this alteration in individuals either fulfilling Amsterdam II criteria or having a tumor demonstrating microsatellite instability (Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Tournier I et al. Hum Mutat, 2008 Dec;29:1412-24). The p.G101S alteration demonstrated deficient mismatch repair efficiency compared to wildtype in one functional study (Tricarico R et al. Hum Mutat, 2017 01;38:64-77). Based on internal structural analysis, the p.G101S alteration has been demonstrated to disrupt a key ATP-binding motif (Ambry internal data; Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5; Borsellini A et al. Nucleic Acids Res, 2022 06;50:6224-6234; Izuhara K et al. J Biol Chem, 2020 08;295:11643-11655). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003451125	SCV004188387	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27363726]. This variant is expected to disrupt protein structure [Myriad internal data].