Submissions for variant NM_000535.7(PMS2):c.251-9C>G

gnomAD frequency: 0.00001  dbSNP: rs1064793639

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484250	SCV000566665	uncertain significance	not provided	2018-10-17	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.251-9C>G or IVS3-9C>G and consists of a C>G nucleotide substitution at the -9 position of intron 3 of the PMS2 gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether PMS2 c.251-9C>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775789	SCV000910238	likely benign	Hereditary cancer-predisposing syndrome	2017-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780634	SCV000918065	uncertain significance	not specified	2018-11-12	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.251-9C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 239860 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.251-9C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001444971	SCV001647989	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915330	SCV004733070	likely benign	PMS2-related condition	2019-12-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).