Submissions for variant NM_000249.4(MLH1):c.1961C>T (p.Pro654Leu)

dbSNP: rs63750726

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075439	SCV000106436	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
GeneDx	RCV000215855	SCV000279084	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased MLH1 expression, decreased stability, reduced interaction with PMS2, disruption of protein localization, and most studies demonstrating reduced mismatch repair activity (Raevaara et al., 2005; Takahashi et al., 2007; Wanat et al., 2007; Drost et al., 2010; Kosinski et al., 2010; Hardt et al., 2011; Andersen et al., 2012; Hinrichsen et al., 2013); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Raevaara et al., 2005; Bozzao et al., 2011; Hardt et al., 2011; Song et al., 2014; Ponz de Leon et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16083711, 22753075, 20533529, 18951446, 17370310, 17192056, 16995940, 24728189, 24362816, 22949387, 21120944, 19669161, 17594722, 17210669, 15849733, 21387278, 23403630, 32658311, 29025352, 20020535, 17510385, 12799449, 21404117, 36356413)
Invitae	RCV001201909	SCV001373001	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 654 of the MLH1 protein (p.Pro654Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MLH1 protein function (PMID: 21404117, 16083711, 20533529, 17510385). This variant has been observed in individual(s) with Lynch syndrome (PMID: 21404117, 16083711). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89959).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000215855	SCV001447878	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415524	SCV002722155	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-21	criteria provided, single submitter	clinical testing	The p.P654L pathogenic mutation (also known as c.1961C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1961. The proline at codon 654 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with Lynch syndrome, including those whose tumors demonstrated microsatellite instability and/or loss of MLH1 protein expression by IHC (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49; Alqahtani M et al. Fam. Cancer, 2018 04;17:197-203). In one meta-analysis, this mutation was detected in 11 unrelated families, nine of whom fulfilled Amsterdam II criteria (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84). Analysis of the mutant protein in bacterial plasmid vectors demonstrated decreased expression of MLH1 and PMS2; however, MMR efficiency was comparable to wild type (Raevaara TE et al. Gastroenterology, 2005 Aug;129:537-49). Similar results were seen in yeast (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). Additional functional assays have shown reduced protein expression in mammalian cells (Hinrichsen I et al. Clin Cancer Res, 2013 May;19:2432-41) as well as 0% interaction with PMS2 and 0% dominant negative mutator effect compared to wild type (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Takahashi M et al. Cancer Res, 2007 May;67:4595-604). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Human Genetics Bochum, Ruhr University Bochum	RCV002463635	SCV002758589	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-06-15	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PM2, PP1, PS3, PM1, PS4
Myriad Genetics, Inc.	RCV002463635	SCV004186318	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV002463635	SCV004192971	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-11	criteria provided, single submitter	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554328	SCV001775544	pathogenic	Breast carcinoma	2021-08-10	no assertion criteria provided	clinical testing	Invasive breast carcinoma ER: + , PR: + , HER2: 0 , KI67%:40