rs878853785

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000249.4(MLH1):​c.2044_2045del​(p.Met682ValfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A681A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

MLH1
NM_000249.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 0.0800
Variant links:
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37048956-CTA-C is Pathogenic according to our data. Variant chr3-37048956-CTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 237329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37048956-CTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MLH1NM_000249.4 linkuse as main transcriptc.2044_2045del p.Met682ValfsTer11 frameshift_variant 18/19 ENST00000231790.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MLH1ENST00000231790.8 linkuse as main transcriptc.2044_2045del p.Met682ValfsTer11 frameshift_variant 18/191 NM_000249.4 P1P40692-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 15, 2024- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jul 25, 2023This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoAug 30, 2018The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 05, 2023This sequence change creates a premature translational stop signal (p.Met682Valfs*11) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 25389437, 25782445). ClinVar contains an entry for this variant (Variation ID: 237329). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 18, 2024The c.2044_2045delAT (p.M682Vfs*11) alteration, located in coding exon 18 of the MLH1 gene, consists of a deletion of 2 nucleotides from position 2044 to 2045, causing a translational frameshift with a predicted alternate stop codon after 11 amino acids. This alteration occurs at the 3' terminus of the MLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 64 amino acids of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients; several whose tumors demonstrated loss of MLH1 and PMS2 staining by immunohistochemistry (IHC) and/or had family histories meeting Amsterdam criteria (Marqués-Lespier, 2014; Cruz-Correa, 2015; Sunga, 2017; Ambry internal data). This alteration has been purported to be a Puerto Rican founder mutation (Rossi, 2017). Based on the available evidence, this alteration is classified as pathogenic. -
Lynch syndrome 1 Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
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SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs878853785; hg19: chr3-37090447; API