Submissions for variant NM_000249.4(MLH1):c.883A>C (p.Ser295Arg)

dbSNP: rs63751598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075901	SCV000106917	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant allele results in splicing abberation leading to premature stop codon: full inactivation of variant allele
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046252	SCV001210147	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Other variant(s) that result in skipping of exon 10 have been determined to be pathogenic (PMID: 15713769, 15849752, 26247049, 26761715; Invitae). This suggests that this variant may also be clinically significant and likely to be disease-causing. Studies have shown that this missense change is associated with altered splicing resulting in exon 10 skipping and introducing a premature termination codon (Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 90408). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16451135, 16830052, 18618713, 18772310, 20223024). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 295 of the MLH1 protein (p.Ser295Arg).
Ambry Genetics	RCV002371910	SCV002683424	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The c.883A>C variant (also known as p.S295R), located in coding exon 10 of the MLH1 gene, results from an A to C substitution at nucleotide position 883. The serine at codon 295 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in an individual with MSI-H, MLH1-absent colorectal cancer diagnosed at age 32, whose family met Amsterdam II criteria (Alemayehu A et al. Genes Chromosomes Cancer, 2008 Oct;47:906-14). RT-PCR and minigene assays indicate that this alteration leads to the skipping of exon 10 and a subsequent frameshift (Kurzawski G et al. Clin Genet, 2006 Jan;69:40-7; Zavodna K et al. Neoplasma, 2006;53:269-76); Soukarieh O et al. PLoS Genet, 2016 Jan;12:e1005756). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV002371910	SCV004359208	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces a serine with an arginine in codon 295 of the MLH1 gene. Functional RNA studies have shown that this variant results in exon 10 skipping (PMID: 16830052, 26761715), predicted to lead to a frameshift and premature translation stop signal. This is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 18618713, http://www.insight-database.org) or colorectal cancer (PMID: 16830052). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005055065	SCV005688971	pathogenic	Inherited MMR deficiency (Lynch syndrome)	2024-09-26	criteria provided, single submitter	clinical testing	PVS1,PM2,PP4
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353502	SCV000592385	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser295Arg variant has been reported in the literature in 3 out of 652 proband chromsomes in individuals who met Amsterdam and Bethesda criteria for HNPCC and was not identified in 60 control chromosomes from these studies (Kurzawski 2006, Alemayehu 2008, Bujalkova 2008). In addition, this variant has been previously reported by our laboratory in two families with a strong family history of colon and endometrial cancer. In one individual tested, a tumor was MSI-H and deficient for MLH1 by immunohistochemistry suggesting absent protein product and a functional consequence of this variant. Furthermore, another variant at the same position (c.883A>G, p.Ser295Gly) has been identified by our laboratory in one family and met our criteria for pathogenicity, increasing the likelihood that this variant also has clinical significance. The p.Ser295Arg variant occurs in the second last base of the exon and this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing further supporting a pathogenic role for this variant. In summary, based on the above information this variant is classified as Pathogenic.