chr3-37047577-GG-ATCTGGACC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1790_1791delGGinsATCTGGACC(p.Trp597TyrfsTer15) variant causes a frameshift, missense 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, missense
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:3
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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28514183, 30787465, 36833268) -
This frameshift variant alters the translational reading frame of the MLH1 mRNA and is predicted to cause 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 an individual with a personal or family history of cancer (PMID: 28514183 (2017)). Based on the available information, this variant is classified as pathogenic. -
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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
The c.1790_1791delGGinsATCTGGACC pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from the deletion of two nucleotides and insertion of 9 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.W597Yfs*15). This alteration has been identified in multiple families that meet Amsterdam criteria for HNPCC/Lynch syndrome and have a family member with a colorectal tumor that displayed loss of both MLH1/PMS2 on immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
This variant deletes two nucleotides and inserts nine 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 and families affected with Lynch syndrome, with tumor data demonstrating loss of MLH1 and PMS2 protein expression via immunohistochemistry analysis (ClinVar SCV000275491.7), as well as in an individual with a personal history or family history of unspecified cancer (PMID: 28514183). 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. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MLH1 c.1790_1791delinsATCTGGACC (p.Trp597TyrfsX15) 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. The variant was absent in 251290 control chromosomes (gnomAD). c.1790_1791delinsATCTGGACC has been reported in the literature in at least an individual undergoing multigene panel testing (Espenschied_2017). In addition, this variant has also been found in a HNPCC family with evidence of co-segregation of variant with the disease in our laboratory (Internal data). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Trp597Tyrfs*15) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28514183). 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: 218018). 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