Submissions for variant NM_000535.7(PMS2):c.353+2T>C

dbSNP: rs111466480

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468932	SCV000552008	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs111466480, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with hyperdiploid acute lymphoblastic leukemia (PMID: 31102422). ClinVar contains an entry for this variant (Variation ID: 411055). Studies have shown that disruption of this splice site results in skipping of exon 4 and activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001020538	SCV001182031	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The c.353+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 4 in the PMS2 gene. This alteration has been detected in individuals whose Lynch syndrome-related tumor demonstrated isolated loss of PMS2 expression on immunohistochemistry (Ambry internal data). This alteration was identified in one control and none of 3030 pancreatic cancer patients undergoing multigene panel testing for hereditary cancer risk (Hu C et al. JAMA. 2018 06;319:2401-2409). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV001020538	SCV001734751	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 4 of the PMS2 gene. Splice site prediction tools predict that this variant weakens the canonical donor site at exon 4 and may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with a Lynch syndrome-associated cancer (ClinVar SCV001182031.3). This variant has been identified in 1/234736 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 Likely Pathogenic.
Revvity Omics, Revvity	RCV001782956	SCV002018872	pathogenic	not provided	2019-01-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001782956	SCV002774372	pathogenic	not provided	2022-09-07	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, 0.0000043 (1/234736 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, this variant has been reported in an individual with high hyperdiploidy-acute lymphoblastic leukemia (HD-ALL) (PMID: 31102422 (2019)). This variant has also been detected in an individual with colon cancer and uterine cancer (Quest Diagnostics internal data). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003449154	SCV004187593	likely pathogenic	Lynch syndrome 4	2023-09-18	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.
All of Us Research Program, National Institutes of Health	RCV004001879	SCV004829737	likely pathogenic	Lynch syndrome	2024-05-10	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 4 of the PMS2 gene. Splice site prediction tools predict that this variant weakens the canonical donor site at exon 4 and may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with a Lynch syndrome-associated cancer (ClinVar SCV001182031.3). This variant has been identified in 1/234736 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 Likely Pathogenic.
GeneDx	RCV001782956	SCV005079319	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29922827, 31102422)