3-37050558-TCACA-T

Position:

• chr3-37050558-TCACA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.2179_2182del​(p.His727PhefsTer55) variant causes a frameshift change. 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. S726S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 5.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 48 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37050558-TCACA-T is Pathogenic according to our data. Variant chr3-37050558-TCACA-T is described in ClinVar as [Pathogenic]. Clinvar id is 90083.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050558-TCACA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.2179_2182del	p.His727PhefsTer55	frameshift_variant	19/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.2179_2182del	p.His727PhefsTer55	frameshift_variant	19/19	1	NM_000249.4	P1

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:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2021	Frameshift variant in the C-terminus predicted to critically alter the protein, as the last 30 amino acids are replaced with 54 different amino acids; Published functional studies demonstrate a damaging effect: inability to induce dominant mutator effect and impaired interaction with PMS2 (Shimodaira 1998, Kondo 2003); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8128251, 12810663, 8630936, 24362816, 9697702, 32719484) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 15, 2022	This frameshift variant alters the translational reading frame of the MLH1 mRNA and causes the premature termination of MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with colorectal cancer and Lynch syndrome (PMID: 8128251 (1994), 8630936 (1996), and 12810663 (2003)). Additionally, experimental evidence suggests that this variant abolishes the interaction between MLH1 and PMS2 (PMID: 12810663 (2003)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 25, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8128251]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change results in a frameshift in the MLH1 gene (p.His727Phefs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MLH1 protein and extend the protein by 24 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 8128251, 8630936, 12810663). This variant is also known as 726–727 del 4bp. ClinVar contains an entry for this variant (Variation ID: 90083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects MLH1 function (PMID: 9697702). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2021

The c.2179_2182delCACA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2179 to 2182, causing a translational frameshift with a predicted alternate stop codon (p.H727Ffs*55). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 24 amino acids. This frameshift impacts the last 30amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been described in a large Native American HNPCC/Lynch syndrome kindred and was shown to segregate with disease in numerous affected individuals (Lynch HT et al. Cancer. 1996 Jan;77(1):30-5). This mutation has also been identified in several individuals whose tumors demonstrated high microsatellite instability and/or loss of MLH1 and PMS2 on immunohistochemistry; some with family histories meeting Amsterdam criteria (Ambry internal data). Functional analysis determined that this alteration has reduced activity in several in vitro studies (Kondo E et al. Cancer Res. 2003 Jun;63(12):3302-8; Shimodaira H et al. Nat. Genet. 1998 Aug;19(4):384-9). Structural analysis shows that this mutation perturbs a known functional domain responsible for binding to PMS2 and removes a cysteine residue shown to be involved in metal binding (Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61; Smith CE et al. PLoS Genet. 2013 Oct;9(10):e1003869). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs267607898; hg19: chr3-37092049;