rs63750035
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1783_1784del(p.Ser595TrpfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 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. P593P) 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.1783_1784del | p.Ser595TrpfsTer14 | frameshift_variant | 16/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.1783_1784del | p.Ser595TrpfsTer14 | frameshift_variant | 16/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461854Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 24, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2022 | Variant summary: MLH1 c.1783_1784delAG (p.Ser595TrpfsX14) 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 251268 control chromosomes (gnomAD). c.1783_1784delAG has been reported in the literature in multiple affected individuals and at least one family meeting Amsterdam criteria for Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome (e.g. Wijnen_1996, Genuardi_1998, Mangold_2005, Barrow_2010). These data indicate that the variant is very likely to be associated with disease. An experimental study using a yeast two-hybrid model system to evaluate the impact of the variant on protein function found that it severely impaired the ability of MLH1 to interact with PMS2 compared to the wild-type protein (e.g. Kondo_2003). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch-like syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
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 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2022 | 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; Identified in individuals with personal or family history of Lynch-associated cancers, including those whose tumors demonstrated loss of MLH1 expression and/or microsatellite instability (Wijnen 1996, Mangold 2005, Yang 2021); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Published functional studies demonstrate defective DNA binding and decreased interaction with PMS2 (Kondo 2003); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 593594 del 2bp; This variant is associated with the following publications: (PMID: 10601588, 8571956, 16216036, 12810663, 34178123) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Ser595Trpfs*14) 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 Lynch syndrome (PMID: 8571956, 12810663, 15849733, 20459533). ClinVar contains an entry for this variant (Variation ID: 89888). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | The c.1783_1784delAG pathogenic mutation, located in coding exon 16 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 1783 to 1784, causing a translational frameshift with a predicted alternate stop codon (p.S595Wfs*14). This mutation has been identified in multiple families who met either Bethesda guidelines or Amsterdam diagnostic criteria for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). In a yeast-based assay, MLH1 protein with this mutation demonstrated decreased interaction with PMS2 compared to wild-type (Kondo E et al. Cancer Res. 2003 Jun 15;63(12):3302-8). 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. - |
Mismatch repair cancer syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at