Submissions for variant NM_000535.7(PMS2):c.2174+1G>T

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002432777	SCV002726674	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-17	criteria provided, single submitter	clinical testing	The c.2174+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 12 of the PMS2 gene. A similar alteration, c.2174+1G>A, has been detected in individuals diagnosed with synchronous primary colon cancers or early-onset colon cancer, whose tumors were MSI-H or showed loss of PMS2 on IHC (Senter L et al. Gastroenterology. 2008 Aug;135(2):419-28; Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095) as well as in patients with CMMR-D, either as compound heterozygous with another PMS2 mutation or in a homozygous state (Vaughn CP et al. Hum Mutat. 2010 May;31(5):588-93; Herkert JC et al. Eur. J. Cancer. 2011 May;47(7):965-82), and a splicing minigene assay demonstrated that c.2174+1G>A caused aberrant splicing (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, c.2174+1G>T is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002481086	SCV002774374	pathogenic	not provided	2021-08-20	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal PMS2 mRNA splicing. To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003454329	SCV004187627	likely pathogenic	Lynch syndrome 4	2023-09-21	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003759713	SCV004471793	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). While functional studies have not been performed to directly test the effect of this variant on PMS2 protein function, this suggests that disruption of this region of the protein is causative of disease. Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 21376568, 26247049). ClinVar contains an entry for this variant (Variation ID: 1787144). Disruption of this splice site has been observed in individuals with colorectal cancer, breast cancer, ovarian cancer, pancreatic cancer, suspected Lynch syndrome, and constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20205264, 21376568, 23012243, 25186627, 26110232, 26681312, 28135145, 30067863). 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 sequence change affects a donor splice site in intron 12 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.