Submissions for variant NM_000535.7(PMS2):c.1144+1G>C

dbSNP: rs373885654

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759912	SCV000889607	likely pathogenic	not provided	2017-12-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378056	SCV001575539	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 619888). 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 (Invitae). Other variant(s) that result in the loss of exon 10 have been determined to be pathogenic (PMID: 16472587, 18602922, 22577899, 23837913, 26318770). This suggests that this variant may also be clinically significant and likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003303232	SCV003995811	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	The c.1144+1G>C intronic variant results from a G to C substitution one nucleotide after 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 donor site. 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, a significant portion of the protein is affected (Ambry internal data). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003453563	SCV004187590	likely pathogenic	Lynch syndrome 4	2023-09-20	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800569	SCV005422076	pathogenic	Hereditary nonpolyposis colon cancer	2024-10-31	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1144+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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of PMS2 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. 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 (Internal data). Deletion of exon 10 has been classified pathogenic by our lab as well as in ClinVar (Variation ID: 583476). The variant was absent in 251134 control chromosomes. To our knowledge, no occurrence of c.1144+1G>C in individuals affected with Lynch Syndrome has been reported. ClinVar contains an entry for this variant (Variation ID: 619888). Based on the evidence outlined above, the variant was classified as pathogenic.