Submissions for variant NM_000249.4(MLH1):c.332C>T (p.Ala111Val)

dbSNP: rs63750539

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075658	SCV000106660	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae	RCV000627728	SCV000543619	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 111 of the MLH1 protein (p.Ala111Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families affected with Lynch syndrome PMID: 10777691, 16451135, 11920650, 17510385, Invitae). ClinVar contains an entry for this variant (Variation ID: 90171) Based on a multifactorial likelihood algorithm using clinical and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this missense change disrupts MLH1 protein function based on yeast and in vitro MMR assays (PMID: 17510385). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002321564	SCV002606264	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-20	criteria provided, single submitter	clinical testing	The p.A111V pathogenic mutation (also known as c.332C>T), located in coding exon 4 of the MLH1 gene, results from a C to T substitution at nucleotide position 332. The alanine at codon 111 is replaced by valine, an amino acid with similar properties. This mutation has been identified in multiple families fulfilling Amsterdam Criteria II (AC II) for a clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) syndrome (Nomura S et al. Biochem. Biophys. Res. Commun. 2000 Apr; 271(1):120-9. Caldes T et al. Int. J. Cancer 2002 Apr; 98(5):774-9). In particular, this mutation was identified in one individual from a family meeting AC II whose tumor studies demonstrated microsatellite instability and loss of MLH1 and PMS2 proteins on immunohistochemistry (Sanchez de Abajo A et al. Oncogene. 2006 Mar 30;25(14):2124-30). In addition to the clinical data, functional analysis of this mutation demonstrated decreased MMR activity in vitro when compared to wildtype (Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604). Furthermore, this alteration has been classified as likely pathogenic 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/]). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV003451134	SCV004187302	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 17510385, 30504929]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20007843, 11920650, 16451135, 28874130, 16288214, 30013564].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353512	SCV000592352	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ala111Val variant has been reported in the literature in 4/594 proband chromosomes from individuals with HNPCC or suspected HNPCC, all of whom met either the Amsterdam criteria II or modified HNPCC criteria. It was not reported in any of the 800 control chromosomes evaluated (Caldes 2002, Chao 2008, Kurzawski 2006, Nomura 2000, Takahashi 2007). In one of these studies, all colorectal tumors belonging to a family with the variant had microsatellite instability at one of the loci evaluated (Caldes 2002). In a functional study that examined the MMR repair ability of the variant, the mutant was found to be have severely compromised repair capacity compared to the wild-type (only 25%). MLH1 expression was found to be between 25-75% (Takahashi 2007). This variant is listed in the dbSNP database (ID#:rs28897759) as coming from a clinical source, but no frequency information was provided, and so the prevalence of this variant in the population is not known. It is not listed in the LOVD or UMD databases. The p.Ala111 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Ala111Val variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In addition, this individual was shown to have MLH1 deficient tumour by IHC, increasing the likelihood this variant may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic.