Submissions for variant NM_000249.4(MLH1):c.83C>T (p.Pro28Leu)

dbSNP: rs63750792

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075881	SCV000106897	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000160552	SCV000213763	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-01	criteria provided, single submitter	clinical testing	The p.P28L pathogenic mutation (also known as c.83C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 83. The proline at codon 28 is replaced by leucine, an amino acid with similar properties. This mutation has been found in multiple families that meet Amsterdam I or Amsterdam II criteria for Lynch syndrome, or had a personal and family history of an HNPCC-related cancer (Kurzawski G et al. J Med Genet. 2002 Oct;39(10):E65; Raevaara, T et al. Gastroenterology. 2005 Aug;129(2):537-49). In addition, individuals with this mutation have concordant tumor studies showing microsatellite instability and/or loss of MLH1 with immunohistochemistry (Raevaara T et al. Gastroenterology. 2005 Aug;129(2):537-49; Spaepen et al. Familial Cancer, 2006 ;5(2):179-89; Mangold et al. J Pathol 2005 Dec;207(4):385-95; Lamberti C et al. Gut 1999 Jun;44(6):839-43). Multiple functional studies have reported that this mutation causes reduced mismatch repair efficiency compared to the wild-type allele (Raevaara T et al. Gastroenterology. 2005 Aug;129(2):537-49; Takahashi M et al. Cancer Res. 2007 May 15;67(10):4595-604). This mutation is in the ATPase domain of MLH1 and other functional studies have reported that it disrupts the interaction of the MLH1 protein with PMS2, supporting that it is pathogenic (Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84; Kondo E et al. Cancer Res. 2003 Jun 15;63(12):3302-8). This alteration has been classified as a class 5 mutation by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075881	SCV000696183	pathogenic	Lynch syndrome	2016-06-16	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.83C>T (p.Pro28Leu) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121156 control chromosomes. This variant has been reported in multiple affected individuals and functional studies showed that variant causes deficient MMR activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000075881	SCV000914313	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000160552	SCV001351149	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 28 in the ATPase domain of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has deficient MMR activity (PMID: 16083711, 17510385) and decreases protein stability and ability to bind EXO1 and/or PMS2 (PMID: 12810663, 17594722, 21404117). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12362047, 16083711, 16736289, 21404117, 23741719), suspected Lynch syndrome (PMID: 21642682, 28874130), or colorectal cancer (PMID: 10323887, 23741719). 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 Pathogenic.
Invitae	RCV001380943	SCV001579171	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 28 of the MLH1 protein (p.Pro28Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 16083711, 16736289). ClinVar contains an entry for this variant (Variation ID: 90388). 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: 10082584, 17210669, 17510385). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800371	SCV002046194	pathogenic	not provided	2020-12-09	criteria provided, single submitter	clinical testing	The variant has been reported in families affected with colorectal cancer in the published literature (PMID: 9298827 (1997), 12362047 (2002), 16451135 (2006), 16736289 (2006), 21404117 (2011), 28874130 (2017)). Additionally, functional studies have observed the variant with reduced mismatch repair activity, expression, and stability (PMID: 21404117 (2011), 17510385 (2007), 16083711 (2005)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Therefore, the variant is classified as pathogenic.