chr3-37004426-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.332C>T(p.Ala111Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A111T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.332C>T | p.Ala111Val | missense_variant | 4/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.332C>T | p.Ala111Val | missense_variant | 4/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 13, 2023 | 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]. - |
Carcinoma of colon Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Lynch syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Jun 21, 2019 | Multifactorial likelihood analysis posterior probability 0.95-0.99 - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 15, 2018 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2018 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at