Submissions for variant NM_000535.7(PMS2):c.706-2A>G

gnomAD frequency: 0.00001  dbSNP: rs745487791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527064	SCV001737904	likely pathogenic	Hereditary nonpolyposis colon cancer	2021-06-15	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.706-2A>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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Two predict the variant creates/strengthen a 3' acceptor site, few nucleotides downstream of the consensus splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7e-06 in 141916 control chromosomes (gnomAD). To our knowledge, no occurrence of c.706-2A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001780396	SCV002024690	likely pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873720	SCV002111995	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-06-19	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1172908). Studies have shown that disruption of this splice site results in retention of intron 6 and skipping of all or part of exon 7 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002368555	SCV002662444	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	The c.706-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 7 in the PMS2 gene. 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 acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 likely pathogenic.
Myriad Genetics, Inc.	RCV004789655	SCV005404113	likely pathogenic	Lynch syndrome 4	2024-08-20	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.