Submissions for variant NM_000535.7(PMS2):c.989-2A>G

dbSNP: rs587779347

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076905	SCV000108403	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000132347	SCV000187436	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	clinical testing	The c.989-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 10 in the PMS2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). This mutation has been reported in an individuals with Lynch syndrome-related cancers whose tumors showed microsatellite instability and/or loss of PMS2 on IHC (Borras E et al. J Med Genet. 2013 Aug;50(8):552-63; Wang Q et al. J Med Genet 2020 07;57(7):487-499). 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 and RNA studies have demonstrated that this alteration results in abnormal splicing (Ambry internal data; Borras E et al. J Med Genet. 2013 Aug;50(8):552-63; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function based on identification of genomic coding exon 10 deletions in Lynch syndrome families with many probands demonstrating isolated loss of PMS2 expression in their tumors by IHC (van der Klift H et al. Genes Chromosomes Cancer. 2005 Oct;44:123-38; Senter L et al. Gastroenterology. 2008 Aug;135:419-428; Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Tomsic J et al. Clin. Genet. 2013 Mar;83:238-43; Brea-Fernandez AJ et al. Clin. Genet. 2014 Jun;85:583-8; Rosty C et al. BMJ Open. 2016 Feb;6:e010293). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000531809	SCV000625713	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-20	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 23709753, 26110232, 30306255, 31992580). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 23709753, 26247049, 30306255). ClinVar contains an entry for this variant (Variation ID: 91386). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.
Color Diagnostics, LLC DBA Color Health	RCV000132347	SCV001339644	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 9 of the PMS2 gene. RNA studies have shown that this variant causes the in-frame skipping of exon 10, resulting in the deletion of the C-terminal ATPase domain (PMID: 23709753, 26247049, 30306255). This variant has been detected in two Spanish families, one of which met Lynch syndrome criteria and the other did not (PMID: 23709753, 30306255) and an individual affected with mismatch repair-deficient endometrial cancer (PMID: 33693762). A different variant, c.989-1G>T, causing the same splicing defect is known to be pathogenic (ClinVar variation ID: 127802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523837	SCV001478144	likely pathogenic	Mismatch repair cancer syndrome 4	2020-12-15	criteria provided, single submitter	research
GeneDx	RCV001556367	SCV001777937	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Canonical splice site variant shown in patient RNA to result in an in-frame skipping of exon 10 (Borras et al., 2013; Bonache et al., 2018), which encodes a part of the critical ATPase domain (Guarne et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Observed as apparently homozygous in a minor with glioblastoma (Fiala et al., 2021) and as heterozygous in individuals with colorectal, endometrial, and other cancers (Borras et al., 2013; Bonache et al., 2018; Wang et al., 2020; Post et al., 2021); This variant is associated with the following publications: (PMID: 24362816, 23709753, 26247049, 26110232, 25512458, 21376568, 30306255, 33693762, 31992580, 34308366, 11574484)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001556367	SCV003799633	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	The PMS2 c.989-2A>G variant (rs587779347) is reported in the literature in individuals and families affected with Lynch syndrome or other cancers (Bonache 2018, Borras 2013, Suerink 2016, Wang 2020). This variant is also reported in ClinVar (Variation ID: 91386), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 9, which is likely to negatively impact gene function. Furthermore, in vitro functional analyses demonstrate exon 10 skipping, which leads to an in-frame deletion but removes part of the binding domain (Bonache 2018, Borras 2013, van der Klift 2015). Based on available information, this variant is considered to be pathogenic. References: Bonache S et al. Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. J Cancer Res Clin Oncol. 2018 Dec;144(12):2495-2513. PMID: 30306255. Borras E et al. Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet. 2013 Aug;50(8):552-63. PMID: 23709753. Suerink M et al. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. Genet Med. 2016 Apr;18(4):405-9. PMID: 26110232. van der Klift HM et al. Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. Mol Genet Genomic Med. 2015 Jul;3(4):327-45. PMID: 26247049. Wang Q et al. Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. J Med Genet. 2020 Jul;57(7):487-499. PMID: 31992580.
Baylor Genetics	RCV003466969	SCV004205421	pathogenic	Lynch syndrome 4	2023-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001556367	SCV004219042	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal PMS2 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with colorectal cancer (CRC) (PMIDs: 31992580 (2020), 23709753 (2013)), breast cancer (BC) (PMID: 30306255 (2018)), endometrial cancer (PMIDs: 33693762 (2021), 31992580 (2020)), bowel cancer (PMID: 31992580 (2020)), and glioblastoma multiforme (PMID: 34308366 (2021)). Functional analysis has demonstrated that this variant causes aberrant splicing and skipping of PMS2 exon 10 (PMIDs: 26247049 (2015), 23709753 (2013)). Based on the available information, this variant is classified as pathogenic.