ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2006+3A>G

dbSNP: rs1064793866
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486350 SCV000567221 uncertain significance not provided 2020-06-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics RCV000574700 SCV000670759 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-27 criteria provided, single submitter clinical testing The c.2006+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 11 in the PMS2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000574700 SCV000686174 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-21 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the +3 position of intron 11 of the PMS2 gene. Splice site prediction tools predict that this variant may not have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV000701178 SCV000829964 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-25 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. 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: 419428). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV000574700 SCV002530249 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000486350 SCV001548658 uncertain significance not provided no assertion criteria provided clinical testing The PMS2 c.2006+3A>G variant was not identified in the literature, nor was it identified in dbSNP, Gene Insight-COGR, Zhejiang University Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors database. The variant was identified in ClinVar (3x as uncertain significance by GeneDx, Ambry Genetics and Color Genomics). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2006+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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