Submissions for variant NM_000535.7(PMS2):c.705+1G>T

dbSNP: rs267608147

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076883	SCV000108378	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV001025973	SCV001188265	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing	The c.705+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the PMS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is insufficient at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on an internal structural analysis, the resulting predicted transcript would substantially disrupt the structure of the PMS2 ATPase domain (Guarné A et al. EMBO J, 2001 Oct;20:5521-31; Ambry internal data). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of PMS2 expression by immunohistochemistry (Clendenning M et al. Hum. Mutat., 2006 May;27:490-5; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV001380258	SCV001578254	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-04	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 16619239, 18602922). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 23629955). ClinVar contains an entry for this variant (Variation ID: 91364). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 6 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).
Myriad Genetics, Inc.	RCV003452995	SCV004187650	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.