ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2174+6T>C (rs587780050)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589942 SCV000149587 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2174+6T>C or IVS12+6T>C and consists of a T>C nucleotide substitution at the +6 position of intron 12 of the PMS2 gene. In-silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). Based on currently available evidence, it is unclear whether PMS2 c.2174+6T>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000225951 SCV000285107 uncertain significance Hereditary nonpolyposis colon cancer 2020-01-07 criteria provided, single submitter clinical testing This sequence change falls in intron 12 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases (rs587780050, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127775). Nucleotide substitutions within 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115678 SCV000601839 uncertain significance not specified 2017-02-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589942 SCV000697334 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2174+6T>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict weakening effect on canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5/94552 control chromosomes at a frequency of 0.0000529, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589942 SCV000889624 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589942 SCV001155027 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

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