Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000535.7(PMS2):c.24-12_107delTGATTTCTCTAGTACAGAACCTGCTAAGGCCATCAAACCTATTGATCGGAAGTCAGTCCATCAGATTTGCTCTGGGCAGGTGGTACTGAGTCTAAGinsAAAT(p.Thr9fs) variant causes a frameshift, splice acceptor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Likely benign.
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]
PMS2 Gene-Disease associations (from GenCC):
Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Lynch syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 755 pathogenic variants in the truncated region.
PP5
Variant 7-6005948-CTTAGACTCAGTACCACCTGCCCAGAGCAAATCTGATGGACTGACTTCCGATCAATAGGTTTGATGGCCTTAGCAGGTTCTGTACTAGAGAAATCA-ATTT is Pathogenic according to our data. Variant chr7-6005948-CTTAGACTCAGTACCACCTGCCCAGAGCAAATCTGATGGACTGACTTCCGATCAATAGGTTTGATGGCCTTAGCAGGTTCTGTACTAGAGAAATCA-ATTT is described in ClinVar as Pathogenic. ClinVar VariationId is 91341.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant involving a canonical splice site reported to result in skipping of exon 2 leading to a null allele in a gene for which loss-of-function is a known mechanism of disease (van der Klift 2010); Observed in individuals with Lynch syndrome (van der Klift 2010, ten Broeke 2015, Suerink 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20186688, 25512458, 26110232) -
Lynch syndrome 4Pathogenic:2
Sep 18, 2023
Myriad Genetics, Inc.
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Apr 29, 2022
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Lynch syndromePathogenic: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 (also interrupts canonical acceptor splice site) -
This variant results in the deletion of part of exon 2 (c.24-12_107delinsAAAT) of the PMS2 gene. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 20186688). ClinVar contains an entry for this variant (Variation ID: 91341). Studies have shown that this variant results in skipping of exon 2, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20186688; internal data). For these reasons, this variant has been classified as Pathogenic. -
The c.24-12_107del96insAAAT pathogenic mutation, located in intron 1 and coding exon 2 of the PMS2 gene, results from the deletion of 96 nucleotides and insertion of 4 nucleotides at positions c.24-12 to c.107. RT-PCR analysis demonstrated that this alteration results in out of frame exon skipping (van der Klift HM et al. Hum. Mutat. 2010 May;31(5):578-87). In addition, this alteration was identified in patients with colorectal cancer, as well as in two siblings with congenital mismatch repair deficiency (CMMR-D) who were positive for a second PMS2 mutation in trans (van der Klift HM et al. Hum. Mutat. 2010 May;31(5):578-87; Bougeard G et al. Fam. Cancer. 2014 Mar;13(1):131-5). In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -