Submissions for variant NM_000535.7(PMS2):c.2445+1G>A

dbSNP: rs876661113

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564513	SCV000670837	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-15	criteria provided, single submitter	clinical testing	The c.2445+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the PMS2 gene. This alteration occurs at the 3' terminus of the PMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12% of the protein. The exact functional effect of this alteration is unknown; however, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386315	SCV001586503	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-04-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 484307). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the retention of 85 base pairs and the production of aberrant transcripts and introduces a new termination codon (PMID: 26247049; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 10037723, 16338176, 20533529, 26116798, 28218421). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003451263	SCV004187609	likely pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	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.
Baylor Genetics	RCV003451263	SCV004207863	likely pathogenic	Lynch syndrome 4	2023-03-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358239	SCV001553914	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 c.2445+1G>A variant was not identified in the literature nor was it identified in the following databases: dbSNP, ClinVar, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2445+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.