ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.23+7G>C

gnomAD frequency: 0.00002  dbSNP: rs878854047
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423172 SCV000521985 likely benign not specified 2016-12-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001088041 SCV000562215 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-12-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759200 SCV000888405 likely benign not provided 2017-09-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000775888 SCV000910368 likely benign Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000423172 SCV000920025 uncertain significance not specified 2023-07-10 criteria provided, single submitter clinical testing Variant summary: PMS2 c.23+7G>C 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. Computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found at a frequency of 1.6e-05 (i.e., 4 heterozygotes) in 250330 control chromosomes, predominantly at a frequency of 9.8e-05 in the South Asian subpopulation (gnomAD v2.1, Exomes dataset). Though this frequency is close to the estimated maximal expected allele frequency of a pathogenic PMS2 variant (1.1e-04), pseudogene interference cannot be ruled out and 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.23+7G>C in individuals affected with Lynch syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
PreventionGenetics, part of Exact Sciences RCV003897873 SCV004717063 likely benign PMS2-related disorder 2023-07-14 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).

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