rs267608156
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1076dupT(p.Leu359PhefsTer6) 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_000535.7 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 exome Cov.: 29
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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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); Variant has been observed in individuals with a personal history of colon and/or endometrial cancer (PMID: 25856668, 18602922); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 18602922, 23012243, 25856668, 29506128, 30161022, 36593122, 37239058, 37308967, 30376427) -
PMS2: PVS1, PM2 -
Lynch syndrome 4 Pathogenic:3
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Lynch syndrome Pathogenic:2
Coding sequence variation resulting in a stop codon -
The c.1076dup (p.Leu359Phefs*6) variant in the PMS2 is located on the exon 10 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Leu359Phefs*6), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer (PMID: 30376427, 37308967, 18602922, 23012243). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar as pathogenic (ID: 91289) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.1076dup (p.Leu359Phefs*6) variant of PMS2 has been classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1076dupT pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a duplication of T at nucleotide position 1076, causing a translational frameshift with a predicted alternate stop codon (p.L359Ffs*6). This alteration (designated c.1076_1077insT) was reported in an individual diagnosed with endometrial cancer showing loss of PMS2 expression at age 49 and also with colon cancer at age 57 (Senter L et al. Gastroenterology 2008 Aug;135:419-28). This mutation has also been identified in other affected and unaffected individuals with Lynch syndrome (Goodenberger ML et al. Genet. Med. 2016 Jan;18:13-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
This variant inserts 1 nucleotide in exon 10 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 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: PMS2 c.1076dupT (p.Leu359PhefsX6) 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 251064 control chromosomes (gnomAD). c.1076dupT has been reported in the literature in at least three individuals affected with Lynch Syndrome-associated cancers, including at least one individual with a personal and family history of Lynch Syndrome-associated cancers and a loss of PMS2 determined by immunohistochemistry (e.g. Senter_2008, Goodenberger_2015, Lowery_2018, ten Broeke_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified 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.Leu359Phefs*6) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 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: 18602922, 23012243). ClinVar contains an entry for this variant (Variation ID: 91289). 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