Submissions for variant NM_000249.4(MLH1):c.1943C>T (p.Pro648Leu)

dbSNP: rs63750610

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075433	SCV000106429	likely pathogenic	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probability > 0.95 (0.989)
Ambry Genetics	RCV000221413	SCV000278137	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-19	criteria provided, single submitter	clinical testing	The p.P648L pathogenic mutation (also known as c.1943C>T) is located in exon 17 of the MLH1 gene. This alteration results from a C to T substitution at nucleotide position 1943. The proline at codon 648 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual diagnosed with microsatellite unstable colorectal cancer at 43 (Raevaara et al. Gastroenterology 2005 Aug; 129(2): 537-49) as well as in cohorts of Lynch syndrome patients and families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20). Functional studies demonstrated decreased protein expression and localization, but intact MMR function. In another study, this alteration showed a negative dominant mutator effect in yeast with MMR activity of 39.2% and MLH1 expression of 25-75% compared to wild type (Takahashi et al. Cancer Res 2007 May 15; 67(10): 4595-604). Another alteration in the same codon, p.P648S, has also been identified in HNPCC/Lynch syndrome families and shown to disrupt interaction between MLH1 and PMS2 in vitro (Bisgaard et al. Hum Mut 2002 Jul; 20(1): 20-7; Raevaara et al. Genes Chromosomes Cancer 2004 Jul; 40(3): 261-5; Belvederesi et al. Eur J Hum Genet 2006 Jul; 14(7): 853-9; Ou et al. Hum Mut 2007 Nov; 28(11): 1047-54). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence and functional studies (Thompson B et al. Hum Mutat. 2013 Jan;34(1):200-9; Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on protein sequence alignment, 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.
Invitae	RCV000812087	SCV000952391	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro648 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15139004, 16083711, 16724012, 18307539, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 16083711, 17510385, 20533529, 21404117, 22753075). 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. ClinVar contains an entry for this variant (Variation ID: 89953). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 11726306, 16083711, 21404117; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 648 of the MLH1 protein (p.Pro648Leu).
Color Diagnostics, LLC DBA Color Health	RCV000221413	SCV001343104	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 648 of the MLH1 protein. The reference amino acid proline 648 is conserved across species (PMID: 12519945, 22908213) and computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID: 16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630). This variant has been reported in three individuals from two families affected with colorectal cancer whose tumors showed features of loss of DNA mismatch repair function (PMID: 16083711, 20020535, 21404117, 23403630, 25871621), and it has been observed in an additional individual with suspected Lynch syndrome (PMID: 27601186). Different variants affecting the same position (p.Pro648Ser and p.Pro648Arg) are considered to be disease-causing (ClinVar variation ID: 17097, 479696) suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269952	SCV001450330	pathogenic	not provided	2016-10-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001269952	SCV002046193	pathogenic	not provided	2021-02-26	criteria provided, single submitter	clinical testing	The variant has been reported in several symptomatic Lynch Syndrome patients in the published literature (PMIDs: 11726306 (2001), 16083711 (2005), 21404117 (2011), 25871621 (2015), and 27601186 (2016)). Functional studies demonstrated decreased protein expression, localization, and MMR function (PMIDs: 16083711 (2005), 17510385 (2007), 20533529 (2010), 21404117 (2011), and 22753075 (2012)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org) and is located in a potentially critical protein domain. Variants affecting the same amino acid position have been described as pathogenic. Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997119	SCV004843242	likely pathogenic	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 648 of the MLH1 protein. The reference amino acid proline 648 is conserved across species (PMID: 12519945, 22908213) and computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant causes reduced MLH1 protein expression and decreased binding to PMS2, although the variant impact on MMR activity is inconclusive (PMID: 16083711, 17510385, 20020535, 20533529, 21404117, 22753075, 23403630). This variant has been reported in three individuals from two families affected with colorectal cancer whose tumors showed features of loss of DNA mismatch repair function (PMID: 16083711, 20020535, 21404117, 23403630, 25871621), and it has been observed in an additional individual with suspected Lynch syndrome (PMID: 27601186). Different variants affecting the same position (p.Pro648Ser and p.Pro648Arg) are considered to be disease-causing (ClinVar variation ID: 17097, 479696) suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477957	SCV000536722	likely pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2016-02-22	no assertion criteria provided	research