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

gnomAD frequency: 0.00001  dbSNP: rs267608172

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076844	SCV000108333	pathogenic	Lynch syndrome	2014-03-14	reviewed by expert panel	research	Interrupts canonical donor splice site
GeneDx	RCV000115677	SCV000149586	pathogenic	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Identified in the heterozygous state in patients with Lynch-related cancers (Senter et al., 2008; Vaughn et al., 2010; Yurgelun et al., 2017; Wang et al., 2020; Xu et al., 2020); Published functional studies demonstrate a damaging effect: aberrant splicing (Herkert et al., 2011; van der Klift et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 18602922, 20205264, 26247049, 26681312, 28726808, 28135145, 25186627, 30067863, 31992580, 33194656, 30787465, 33087929, 21376568)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076844	SCV000271439	pathogenic	Lynch syndrome	2019-04-19	criteria provided, single submitter	clinical testing	The c.2174+1G>A variant in PMS2 has been reported in 1 heterozygous individual with PMS2-associated cancers, and in 1 compound heterozygous and 1 homozygous individual with constitutional mismatch repair deficiency (Senter 2008, Herkert 2011). It segregated in a compound heterozygous state with disease in one affect sibling (Herkert 2011). It has also has been identified in 1/30070 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.2174+1G>A variant may impact the protein (Van Der Klift, 2015). In addition, it was classified as Pathogenic on April 16, 2014 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108333.3). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based. ACMG/AMP criteria applied: PM2, PS4_Supporting, PM3_Supporting, PVS1.
Ambry Genetics	RCV000218995	SCV000272981	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The c.2174+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). A splicing minigene assay and RNA analysis has demonstrated aberrant splicing (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several whose tumors demonstrated loss of PMS2 by immunohistochemistry (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; Brand R et al. Cancer, 2018 09;124:3520-3527; Wang Q et al. J Med Genet, 2020 07;57:487-499). This mutation has also been detected in the homozygous and compound heterozygous state in multiple patients with constitutional mismatch repair deficiency (CMMR-D) syndrome (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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000409361	SCV000488693	pathogenic	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000539044	SCV000625591	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-15	criteria provided, single submitter	clinical testing	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. 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. 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). ClinVar contains an entry for this variant (Variation ID: 91329). 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). 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076844	SCV000697333	pathogenic	Lynch syndrome	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2174+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. RNA analysis was performed to study the effect of c.2174+1G>A on mRNA splicing and to confirm that this mutation is located in PMS2 and not in its highly homologous pseudogene PMS2CL. The variant allele was found at a frequency of 1.7e-05 in 239230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (1.7e-05 vs 0.00011), allowing no conclusion about variant significance. c.2174+1G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and features of CMMRD. Specifically, the variant has been cited in multiple patients in both heterozygous, compound heterozygous (in trans with a second pathogenic PMS2 variant), and homozygous state, several of whom have loss of PMS2 via IHC. Carrying two MMR mutations in PMS2 in trans has been associated with constitutional mismatch repair-deficiency, which is characterized by colonic polyposis and hematologic, brain and gastrointestinal malignancies, as well as neurofribromas, which present at a young age and thus both mutations may be explaining the phenotype in the individuals reported. The variant alone was found in unaffected parents of probands, further supporting the idea that the variant is involved in constitutional mismatch repair-deficiency. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, but does not provide convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000115677	SCV001247256	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149757	SCV003838382	pathogenic	Breast and/or ovarian cancer	2022-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409361	SCV004019883	likely pathogenic	Lynch syndrome 4	2023-04-05	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	RCV000409361	SCV004205506	pathogenic	Lynch syndrome 4	2023-07-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115677	SCV004218977	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-donor site and interferes with normal PMS2 mRNA splicing. The frequency of this variant in the general population, 0.000016 (4/244414 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 27435373 (2016), 26681312 (2015)), breast cancer (PMID: 25186627 (2015)), ovarian cancer (PMID: 20205264 (2010)), and pancreatic cancer (PMID: 30067863 (2018)). The variant has also been reported in an individual with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 21376568 (2011)). Splicing analysis studies have shown that this variant results in aberrant splicing (PMID: 26247049 (2015), 21376568 (2011)). Based on the available information, this variant is classified as pathogenic.
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000115677	SCV000925691	not provided	not provided		no assertion provided	in vitro
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000115677	SCV001740282	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000115677	SCV001957416	pathogenic	not provided		no assertion criteria provided	clinical testing