Submissions for variant NM_000535.7(PMS2):c.1144+1G>A

gnomAD frequency: 0.00001  dbSNP: rs373885654

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000149895	SCV000196743	likely pathogenic	Lynch syndrome	2014-06-01	criteria provided, single submitter	research
GeneDx	RCV000213090	SCV000279941	pathogenic	not provided	2017-03-20	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.1144+1G>A or IVS10+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 10 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in two individuals included in a population screening cohort, however personal and family cancer histories were not provided (Amendola 2015). Based on the current evidence, we consider this variant to be pathogenic.
Invitae	RCV001044002	SCV001207774	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs373885654, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with colorectal cancer and a personal and/or family history of breast and/or ovarian cancer (PMID: 29566657, 30521064). ClinVar contains an entry for this variant (Variation ID: 162508). 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 (Invitae). Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000213090	SCV001474273	likely pathogenic	not provided	2020-05-28	criteria provided, single submitter	clinical testing	The PMS2 c.1144+1G>A variant (rs373885654) is reported in the literature in an individual with colorectal cancer (Jiang 2019) and an individual with breast cancer (Wang 2018). This variant is also reported in ClinVar (Variation ID: 162508). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 10, which is likely to negatively impact gene function. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Jiang W et al. Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features. Int J Cancer. 2019;144(9):2161-2168. Wang YA et al. Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer. 2018;18(1):315.
Revvity Omics, Revvity	RCV000213090	SCV002018891	pathogenic	not provided	2019-05-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453477	SCV002615802	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-05-13	criteria provided, single submitter	clinical testing	The c.1144+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the PMS2 gene. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). 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 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 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 immunohistochemistry (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 was identified in a 51 year old Chinese male patient whose colorectal tumor demonstrated loss of MSH2 and PMS2 expression on immunohistochemistry (IHC) (Jiang W et al. Int. J. Cancer, 2019 05;144:2161-2168). 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.
Myriad Genetics, Inc.	RCV003453108	SCV004187640	likely pathogenic	Lynch syndrome 4	2023-09-20	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.
Baylor Genetics	RCV003453108	SCV004203431	pathogenic	Lynch syndrome 4	2020-12-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000149895	SCV004848351	likely pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The c.1144+1G>A variant in PMS2 has been reported in one individual with PMS2-associated cancer (Wu 2019). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 162508). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch Syndrome. ACMG/AMP Criteria applied: PVS1, PM2.