Submissions for variant NM_000249.4(MLH1):c.1942C>T (p.Pro648Ser)

dbSNP: rs63750899

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075432	SCV000106428	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000162472	SCV000212839	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-28	criteria provided, single submitter	clinical testing	The p.P648S pathogenic mutation (also known as c.1942C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1942. The proline at codon 648 is replaced by serine, an amino acid with similar properties. This mutation has been reported in multiple individuals satisfying clinical diagnostic criteria for HNPCC/Lynch syndrome (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): 104754). Tumor studies in some of these individuals demonstrated microsatellite instability and loss of MLH1 protein expression on immunohistochemistry. In addition, this mutation has been shown to disrupt interaction between MLH1 and PMS2 in vitro (Belvederesi et al. Eur J Hum Genet 2006 Jul; 14(7): 853-9). 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 BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001040524	SCV001204103	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 648 of the MLH1 protein (p.Pro648Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch Syndrome (PMID: 12112654, 15139004, 16724012). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17097). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15139004, 16724012, 21404117). 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: 11726306, 16083711, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284501	SCV001470330	pathogenic	not provided	2019-12-27	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals
Myriad Genetics, Inc.	RCV000018629	SCV004188465	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. 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].
OMIM	RCV000018629	SCV000038912	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2004-07-01	no assertion criteria provided	literature only
OMIM	RCV001267884	SCV001446363	pathogenic	Mismatch repair cancer syndrome 1	2004-07-01	no assertion criteria provided	literature only