Submissions for variant NM_000535.7(PMS2):c.538-1G>C

gnomAD frequency: 0.00001  dbSNP: rs988423880

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772161	SCV000905277	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818274	SCV000958876	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with constitutional mismatch repair deficiency syndrome (PMID: 24440087). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 434027). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523839	SCV001478146	pathogenic	Mismatch repair cancer syndrome 4	2020-12-15	criteria provided, single submitter	research
Ambry Genetics	RCV000772161	SCV002646986	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The c.538-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 6 of the PMS2 gene. This mutation has been reported in a child with Constitutional MisMatch Repair Deficiency (CMMRD) syndrome in conjunction with a PMS2 gross deletion mutation (Bakry D et al. Eur J Cancer, 2014 Mar;50:987-96). The child was diagnosed with cafe-au-lait macules, T-cell lymphoblastic lymphoma at age 3.5y and GI polyposis at age 11.5y. IHC staining of a GI polyp and normal tissue showed isolated loss of the PMS2 protein. There was no reported family history of cancer. 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; 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 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). 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.
GeneDx	RCV003126761	SCV003803442	likely pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28873162, 11574484, 35585047, 34308366, 24440087)
Myriad Genetics, Inc.	RCV003449416	SCV004187605	likely pathogenic	Lynch syndrome 4	2023-09-19	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	RCV003449416	SCV004207886	pathogenic	Lynch syndrome 4	2022-08-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806377	SCV005429644	likely pathogenic	Lynch syndrome	2024-06-09	criteria provided, single submitter	clinical testing	This variant causes a G>C nucleotide substitution at the -1 position of intron 5 of the PMS2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to abolish the acceptor site at exon 6 and result in in-frame exon skipping and a disrupted protein product. This variant has been reported in trans with a PMS2 deletion of exons 6-8 in an individual affected with constitutional mismatch repair disorder (PMID: 24440087). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.538-1G>A, c.538-2A>T, c.538-2A>C, and c.538-2A>G, are described to be disease-causing (ClinVar variation ID: 948334, 2573263, 926801, 411028). Loss of PMS2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500977	SCV000592926	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The c.538-1G>C variant was identified in the literature in 1 of 36 chromosomes from individuals with features of bi-allelic mismatch repair syndrome (Bakry_2014_24440087). The phenotypes included: T-cell lymphoblastic lymphoma, GI polyposis, and Café-au-lait macules. The variant was identified as co-occuring with the c.538-?_903+?del(exon 6-8 del), variant, classified as pathogenic, in a non-consanguineous family, and consistent with recessive inheritance as observed in biallelic mismatch repair syndrome. The c.538-1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. 5 out of 5 splicing programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict altered splicing of this variant increasing the likelihood this variant is pathogenic. In summary, based on the above information, this variant is classified as pathogenic.