Submissions for variant NM_000535.7(PMS2):c.251-2A>C

dbSNP: rs587779340

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219075	SCV000278228	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	The c.251-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 4 in the PMS2 gene. This mutation has been detected in several individuals with early-onset colorectal cancer; in one individual, the tumor showed high microsatellite instability (MSI-H) and isolated loss of PMS2 protein expression on IHC (Niessen RC et al. Genes Chromosomes Cancer. 2009 Apr;48:322-9; ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33:319-25). In addition, two other alterations at this position (c.251-2A>G and c.251-2A>T) have been reported as pathogenic in HNPCC and CMMR-D cohorts (Senter L et al. Gastroenterology. 2008 Aug;135:419-28; Herkert JC et al. Eur. J. Cancer. 2011 May;47:965-82; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 pathogenic.
CSER _CC_NCGL, University of Washington	RCV000735964	SCV000864153	likely pathogenic	Polyp of colon	2016-06-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 58 year old female with a personal history of 21-50 colon polyps and family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Diagnostics, LLC DBA Color Health	RCV000219075	SCV000904810	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the -2 position of intron 3 of the PMS2 gene. Splice site prediction tools predict 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 likely to cause out-of-frame skipping of exon 4 and expected to result in an absent or disrupted protein product. This variant has been observed in individuals affected with Lynch syndrome (PMID: 19132747, 25980754, 27435373; ClinVar SCV002235355.2), as well as in a compound heterozygous state with a known pathogenic PMS2 variant in a family affected with autosomal recessive constitutional mismatch repair deficiency syndrome (PMID: 18602922). This variant has not been identified 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.
GeneDx	RCV001530037	SCV001795512	pathogenic	not provided	2021-03-17	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32719484, 19132747, 25525159)
Invitae	RCV001854704	SCV002235355	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-04-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 233781). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 18602922, 19132747, 27435373; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 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).
Revvity Omics, Revvity	RCV001530037	SCV003809954	likely pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454656	SCV004187571	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.
GenomeConnect, ClinGen	RCV001249235	SCV001423170	not provided	Hereditary nonpolyposis colon cancer		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 01-25-2019 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530037	SCV001744557	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530037	SCV001958082	pathogenic	not provided		no assertion criteria provided	clinical testing