ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.445del (p.Tyr149fs) (rs769742496)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412857 SCV000490728 pathogenic not provided 2016-02-26 criteria provided, single submitter clinical testing This deletion of one nucleotide in PMS2 is denoted c.445delT at the cDNA level and p.Tyr149ThrfsX52 (Y149TfsX52) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCCCC[T]ACCCC. The deletion causes a frameshift, which changes a Tyrosine to a Threonine at codon 149, and creates a premature stop codon at position 52 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. we consider this variant to be pathogenic.
Invitae RCV000815178 SCV000955625 pathogenic Hereditary nonpolyposis colon cancer 2019-11-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr149Thrfs*52) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 372468). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001022512 SCV001184262 pathogenic Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV001193216 SCV001361925 likely pathogenic Hereditary nonpolyposis colon cancer 2019-09-04 criteria provided, single submitter clinical testing Variant summary: PMS2 c.445delT (p.Tyr149ThrfsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.697C>T (p.Gln233X), c.735dupG (p.Pro246fsX3), c.765C>A, (p.Tyr255X)). The variant allele was found at a frequency of 4e-06 in 250958 control chromosomes (gnomAD) and has been reported in the literature in an individual affected with breast cancer (Roberts_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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