Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.1730dupA(p.Arg578AlafsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K577K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-5987034-C-CT is Pathogenic according to our data. Variant chr7-5987034-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 91310.Status of the report is reviewed_by_expert_panel, 3 stars.
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Sep 20, 2023
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary nonpolyposis colon cancer Pathogenic:1
Nov 20, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: PMS2 c.1730dupA (p.Arg578AlafsX3) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251352 control chromosomes. c.1730dupA has been reported in the literature as a biallelic genotype alongside another pathogenic PMS2 variant in two siblings affected with features of Constitutional Mismatch Repair Deficiency (CMMRD) (Auclair_2007 cited in Bodo_2015 and preumed overlap with Suerink_2019). The following publications have been ascertained in the context of this evaluation (PMID: 17557300, 26116798, 31204389). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on PMS2 loss of function as an established mechanism of disease and the evidence outlined above, the variant was classified as pathogenic. -
Lynch syndrome Pathogenic:1
Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: research
Coding sequence variation resulting in a stop codon -
not provided Pathogenic:1
Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Arg578Alafs*3) 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 colorectal cancer and constitutional mismatch repair deficiency (CMMR-D) associated tumors (PMID: 17557300, 22585707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91310). For these reasons, this variant has been classified as Pathogenic. -