ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1778del (p.Lys593fs) (rs766389591)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217805 SCV000279676 likely pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing This deletion of one nucleotide in PMS2 is denoted c.1778delA at the cDNA level and p.Lys593SerfsX2(K593SfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is CAAA[A]GTTA. The deletion causes a frameshift, which changes a Lysine to a Serine at codon 593, and creates a premature stop codon at position 2 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Color RCV000579913 SCV000686161 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Invitae RCV000807900 SCV000947980 pathogenic Hereditary nonpolyposis colon cancer 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys593Serfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs766389591, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234673). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217805 SCV001134586 likely pathogenic not provided 2019-06-20 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The best available variant frequency is uninformative.
Ambry Genetics RCV000579913 SCV001173690 pathogenic Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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