Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.1778del(p.Lys593SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K593K) 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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 7-5986986-CT-C is Pathogenic according to our data. Variant chr7-5986986-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
All of Us Research Program, National Institutes of Health
Aug 23, 2023
This variant deletes 1 nucleotide in exon 11 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. To our knowledge, this variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/251436 chromosomes 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. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
May 08, 2019
The p.Lys593SerfsX2 variant in PMS2 has not been previously reported in individuals with Lynch syndrome but has been identified in 1/113742 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 234673). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 593 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2. -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 20, 2019
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is uninformative. -
Likely pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Dec 03, 2015
This deletion of one nucleotide in PMS2 is denoted c.1778delA at the cDNA level and p.Lys593SerfsX2(K593SfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is CAAA[A]GTTA. The deletion causes a frameshift, which changes a Lysine to a Serine at codon 593, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant. -
This variant deletes 1 nucleotide in exon 11 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. To our knowledge, this variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/251436 chromosomes 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Oct 07, 2022
The c.1778delA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1778, causing a translational frameshift with a predicted alternate stop codon (p.K593Sfs*2). 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. -
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 234673). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs766389591, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys593Serfs*2) 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). -
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Feb 24, 2022
- -
Lynch syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Sep 20, 2023
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -