Submissions for variant NM_000535.7(PMS2):c.989-1G>T

dbSNP: rs587780064

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115713	SCV000149622	pathogenic	not provided	2021-05-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24689082, 25345868, 30322717, 25525159, 20587412, 19039682, 26247049, 24790682, 26681312, 29625052)
Ambry Genetics	RCV000563759	SCV000663469	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	The c.989-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 10 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (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 altered amino acid sequence is unknown; however, a significant portion of the protein is affected (Ambry internal data). This mutation has been detected in numerous individuals with Lynch syndrome and has been described as a founder mutation in the Norwegian population (Grindedal EM et al. Hered Cancer Clin Pract. 2014 Apr 21;12(1):12). It has also been detected in the homozygous state in a family with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (Sjursen W et al. Fam Cancer. 2009;8(3):179-86). Tumor analyses from affected individuals with this mutation have shown that the majority of tumors display microsatellite instability but normal PMS2 protein expression by immunohistochemistry. Functional analyses, using minigene assays and RT-PCR analyses of patient RNA, detected abnormal transcripts with partial or complete skipping of exon 10 (Sjursen W et al. Fam Cancer. 2009;8(3):179-86; van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3(4):327-45). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000563759	SCV000686265	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 9 of the PMS2 gene. RNA studies on patient-derived RNA and minigene splicing assay have shown that this variant resulted in aberrant mRNA predicted to cause in-frame deletion in the ATPase domain (PMID: 19039682, 26247049). This variant has been reported in a homozygous carrier affected with Turcot syndrome (PMID: 19039682) and multiple individuals affected with Lynch syndrome-associated cancer (PMID: 19723918, 24790682) and colon polyps (PMID: 26681312). The majority of the tumors exhibited microsatellite instability and this variant is reported to segregate with disease (PMID: 24790682). This variant has been identified in 1/246764 chromosomes 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.
Invitae	RCV000697325	SCV000825927	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-15	criteria provided, single submitter	clinical testing	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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with Turcot syndrome (PMID: 19039682, 19723918, 24790682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127802). 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: 19039682, 26247049; Invitae). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258088	SCV001434930	pathogenic	Lynch syndrome 4	2019-08-20	criteria provided, single submitter	clinical testing	This variant is located in the canonical splice acceptor site in intron 9 of the PMS2 gene and is predicted to lead to abnormal splicing. This variant is located at extremely low frequency in the gnomAD population database (1/246764 alleles). It has been reported in several Norwegian families affected with Lynch syndrome (PMID: 19039682, 24790682, 19723918), particularly cancers of the colon, endometrium, breast, stomach, and prostate. Interestingly, immunohistochemistry (IHC) studies of cancers with this variant were normal but they demonstrated microsatellite instability (MSI) (PMID: 24790682). In vitro functional studies show this variant leads to skipping of exon 10 which is part of an important functional domain of the protein product (PMID: 26247049). This PMS2 variant is thus considered pathogenic.
Revvity Omics, Revvity	RCV000115713	SCV002019445	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997296	SCV004842579	pathogenic	Lynch syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing is an established mechanism of disease. This prediction has been confirmed by RNA splicing studies (PMID: 19039682, 26247049, 32849802). Different variants at this splicing acceptor site have been reported in association with disease and are independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with Lynch syndrome and is a known founder mutation (PMID: 19039682, 24790682, 25345868, 26110232, 31204389). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been reported to co-segregate with disease in affected individuals in one family (PMID: 24790682).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003997296	SCV004848355	pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The c.989-1G>T variant in PMS2 has been reported in 6 probands with Lynch syndrome and segregated with disease in >15 affected individuals from 2 families (Grindedal 2009, Hansen 2014, Grindedal 2014, Susswein 2015, Carter 2018). This variant was also reported in one homozygous individual who had >8 Lynch-associated cancers, consistent with constitutional mismatch repair deficiency (Sjursen 2009). It was absent from large population studies, but reported in ClinVar (ClinVar ID 127802). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. RNA-based studies showed full or partial skipping of exon 10 (Hansen 2014, van der Klift 2015), and a study of microsatellite instability in carriers of this variant demonstrated that 19/23 cancers were microsatellite unstable, consitent with loss of protein function (Grindedal 2014). Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate, PS3_Supporting.
GeneReviews	RCV001804845	SCV002054087	not provided	Lynch syndrome 1		no assertion provided	literature only