rs267607903

Variant names:

• chr3-37050575-T-TAAAC
• rs267607903
• NM_000249.4:c.2195_2198dupAACA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.2195_2198dupAACA​(p.His733GlnfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 3.80

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 14 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37050575-T-TAAAC is Pathogenic according to our data. Variant chr3-37050575-T-TAAAC is described in ClinVar as [Pathogenic]. Clinvar id is 90088.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.2195_2198dupAACA	p.His733GlnfsTer14	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.2195_2198dupAACA	p.His733GlnfsTer14	frameshift_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Apr 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2, PS4_moderate, PVS1_strong -

May 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 24 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream (Landrum 2016); Published functional studies demonstrate a damaging effect: decreased PMS2 interaction (Kondo 2003); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Risinger 1996, Kondo 2003, Kunstmann 2004, Chong 2009, Schiavi 2015, Rosty 2016, Yurgelun 2017); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12810663, 15217520, 26895986, 19459153, 26628864, 8646682, 28135145, 32659967) -

Jun 19, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

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 premature protein truncation. -

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

Frameshift interrupting C-terminus interaction domain. Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His733Glnfs*14) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8646682, 12658575, 15217520, 15849733, 19459153). It has also been observed to segregate with disease in related individuals. 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. ClinVar contains an entry for this variant (Variation ID: 90088). RNA analysis performed to evaluate the impact of this premature translational stop signal 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

Aug 06, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2195_2198dupAACA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a duplication of AACA at nucleotide position 2195, causing a translational frameshift with a predicted alternate stop codon (p.H733Qfs*14). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 24 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, several with tumors exhibiting loss of MLH1 on immunohistochemistry (Syngal S et al. JAMA, 1999 Jul;282:247-53; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Kunstmann E et al. BMC Med. Genet., 2004 Jun;5:16; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Ponti G et al. Clin Genet, 2015 Jun;87:507-16; Schiavi A et al. Curr Oncol, 2015 Oct;22:317-25; Rosty C et al. BMJ Open, 2016 Feb;6:e010293; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Lawrence J et al. Curr Oncol, 2021 01;28:509-522). This alteration is posited as a French-Canadian founder mutation (Chong G et al. Hum. Mutat., 2009 Aug;30:E797-812). 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. -

Lynch syndrome 1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607903; hg19: chr3-37092066;