rs267607898

Variant names:

• chr3-37050558-TCACA-T
• rs267607898
• NM_000249.4:c.2179_2182delCACA

Your query was ambiguous. Multiple possible variants found:

• chr3-37050558-TCACA-T
• chr3-37050558-TCACA-TCA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.2179_2182delCACA​(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. H727H) has been classified as 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
• Publications: 6 publications found

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]

MLH1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 59 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 VariationId is 90083.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2179_2182delCACA	p.His727PhefsTer55	frameshift_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2179_2182delCACA	p.His727PhefsTer55	frameshift_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

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

Jan 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MLH1 c.2179_2182del (p.His727Phefs*55) variant alters the translational reading frame of the MLH1 mRNA and causes the premature termination of MLH1 protein synthesis. This variant has been reported in the published literature in in individuals and families with colorectal cancer and Lynch syndrome (PMIDs: 33676177 (2021), 12810663 (2003), 8630936 (1996), and 8128251 (1994)). Additionally, experimental evidence suggests that this variant abolishes the interaction between MLH1 and PMS2 (PMID: 12810663 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2

Mar 06, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. 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 gene product 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). RNA analysis performed to evaluate the impact of this frameshift on mRNA splicing indicates it does not significantly alter splicing (internal data). 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

Oct 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607898; hg19: chr3-37092049; COSMIC: COSV99212457;