Submissions for variant NM_000535.7(PMS2):c.804-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1307026290

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001054912	SCV001219271	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome (PMID: 19156169). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 850689). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002409456	SCV002675839	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-19	criteria provided, single submitter	clinical testing	The c.804-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 in the PMS2 gene. This mutation was identified in trans with another PMS2 mutation in an individual with CMMRD whose colon tumor and normal tissue both demonstrated microsatellite instability; this individual's brother was diagnosed with MSI-H glioblastoma at age 10, and both PMS2 mutations were present in his tumor (Giunti L et al. Eur J Hum Genet, 2009 Jul;17:919-27). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel 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.
Myriad Genetics, Inc.	RCV003455250	SCV004187611	likely pathogenic	Lynch syndrome 4	2023-09-19	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	RCV003455250	SCV004205385	pathogenic	Lynch syndrome 4	2023-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994200	SCV004813647	likely pathogenic	Hereditary nonpolyposis colon cancer	2024-02-22	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.804-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site. Two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251328 control chromosomes (gnomAD). c.804-2A>G has been reported in the literature in individuals affected with features of constitutional mismatch repair deficiency syndrome with another pathogenic variant in trans (Giunti_2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19156169). ClinVar contains an entry for this variant (Variation ID: 850689). Based on the evidence outlined above, the variant was classified as likely pathogenic.