Submissions for variant NM_000535.7(PMS2):c.803+1G>A

dbSNP: rs1562669585

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068955	SCV001234092	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 862267). Disruption of this splice site has been observed in individuals with colorectal cancer (PMID: 31992580; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800953	SCV002046267	likely pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. To the best of our knowledge, the variant has not been reported in individuals with PMS2-related conditions in the published literature. Based on the available information, we predict that the variant is likely pathogenic.
Myriad Genetics, Inc.	RCV003455298	SCV004187635	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	RCV003455298	SCV004207854	pathogenic	Lynch syndrome 4	2023-04-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004944847	SCV005472436	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-26	criteria provided, single submitter	clinical testing	The c.803+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the PMS2 gene. 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. 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 and may also create or strengthen a novel splice donor site resulting in a protein with an in-frame deletion; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.