rs63750855
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1489del(p.Arg497GlyfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T495T) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.1489del | p.Arg497GlyfsTer11 | frameshift_variant | 13/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1489del | p.Arg497GlyfsTer11 | frameshift_variant | 13/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | MLH1 (Arg497fs): This sequence change creates a premature translational stop signal (p.Arg497Glyfs*11) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with Lynch syndrome and Muir-Torre syndrome (PMID: 15872200, 18270343). ClinVar contains an entry for this variant (Variation ID: 89752) with 3 submissions, all pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). Therefore, this variant has been classified as Pathogenic. . - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 20, 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 | Coding sequence variation resulting in a stop codon - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2020 | 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 been reported in individuals affected with Lynch syndrome and Muir-Torre syndrome (PMID: 15872200, 18270343). ClinVar contains an entry for this variant (Variation ID: 89752). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Arg497Glyfs*11) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2021 | The c.1489delC pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.R497Gfs*11). This mutation was identified in a patient with colorectal cancer at 46 and Muir-Torre phenotype (Hampel H et al. N. Engl. J. Med. 2005 May;352:1851-60; South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-81). This mutation was also reported in a patient with endometrial cancer showing absent MLH1 and PMS2 protein expression by immunohistochemistry (Moline J et al. Gynecol. Oncol. 2013 Jul;130:121-6). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at