rs63749868
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1772_1775delATAG(p.Asp591ValfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000249.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MLH1-related cancers (PMID: 26248088, 29228462); This variant is associated with the following publications: (PMID: 26248088, 8872463, 12810663, 29228462, 17312306) -
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Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 4 nucleotides in exon 16 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome, colorectal, or endometrial cancer (PMID: 8872463, 17312306, 26248088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The c.1772_1775delATAG pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 1772 to 1775, causing a translational frameshift with a predicted alternate stop codon (p.D591Vfs*24). This mutation has been previously identified in multiple unrelated individuals, whose personal and family history either met Amsterdam I/II criteria or Bethesda guidelines for testing for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Lagerstedt Robinson K et al. J Natl Cancer Inst. 2007 Feb 21; 99(4): 291-9; Moslein G et al. Hum. Mol. Genet. 1996 Sep;5:1245-52; Guindalini RS et al. Gastroenterology. 2015 Nov;149:1446-53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MLH1 c.1772_1775delATAG (p.Asp591ValfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. c.1772_1775delATAG has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example, Moslein_1996, Lagerstedt Robinson_2007, Guindalini_2015). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Lynch-like syndrome Pathogenic:1
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Lynch syndrome Pathogenic:1
Coding sequence variation resulting in a stop codon -
MLH1-related disorder Pathogenic:1
The MLH1 c.1772_1775delATAG variant is predicted to result in a frameshift and premature protein termination (p.Asp591Valfs*24). This variant, also referred to as 590-591 delTAGA, has been reported to be pathogenic for colorectal cancer (Moslein et al 1996. PubMed ID: 8872463; Kondo E et al 2003. PubMed ID: 12810663; Table S1 Guindalini RS et al 2015. PubMed ID: 26248088). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in MLH1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asp591Valfs*24) 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 colorectal cancer and Lynch syndrome (PMID: 8872463, 12810663, 17312306, 26248088). 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 590–591 del TAGA. ClinVar contains an entry for this variant (Variation ID: 89886). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at