rs267607903
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000249.4(MLH1):c.2195_2198dupAACA(p.His733fs) 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
NM_000249.4 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461840Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727224
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 19, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 12, 2024 | PP1_strong, PM2, PS4_moderate, PVS1_strong - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2021 | 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) - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
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 premature protein truncation. - |
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Frameshift interrupting C-terminus interaction domain. Multifactorial likelihood analysis posterior probability >0.99 - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 21, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 90088). 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. This variant is not present in population databases (gnomAD no frequency). 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 06, 2021 | 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
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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