ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2445+1G>C (rs876661113)

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Total submissions: 3
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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 2019-09-06 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: 5/5 tools predict that 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 (gnomAD). To our knowledge, no occurrence of c.2445+1G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
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.

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