Submissions for variant NM_000535.7(PMS2):c.2445+1G>C

dbSNP: rs876661113

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234016	SCV000285121	likely pathogenic	Lynch syndrome	2015-11-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 14. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in PMS2 are known to be pathogenic (PMID:20205264). For these reasons, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193217	SCV001361926	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2445+1G>C 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: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 194842 control chromosomes. To our knowledge, no occurrence of c.2445+1G>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sema4, Sema4	RCV002255326	SCV002530307	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	curation
GeneDx	RCV002291604	SCV002584138	pathogenic	not provided	2022-10-13	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
Myriad Genetics, Inc.	RCV003454706	SCV004187630	likely pathogenic	Lynch syndrome 4	2023-09-25	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354824	SCV001549534	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 c.2445+1G>T variant was identified in 3 of 1152 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome or colorectal cancer (Niessen 2009, Suerink 2015, ten Broeke 2015). The variant was also identified in dbSNP (ID: rs876661113) as "With Likely pathogenic, Pathogenic allele" and ClinVar (classified as pathogenic by Invitae, ARUP, Ambry Genetics and GeneDx). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.2445+1G>T variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. Further, RNA-based mutation scanning found this variant produced two aberrant splice products in cultured lymphocyte RNA (van der Klift 2015). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.