rs863225384
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.793delC(p.Arg265ValfsTer3) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000249.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The MLH1 c.793del (p.Arg265Valfs*3) 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 individuals with MLH1-related conditions in the published literature. 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 likely pathogenic. -
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Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg265Valfs*3) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.793delC pathogenic mutation, located in coding exon 10 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 793, causing a translational frameshift with a predicted alternate stop codon (p.R265Vfs*3). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at