ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.903G>A (p.Lys301=) (rs267608153)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228489 SCV000285162 likely pathogenic Hereditary nonpolyposis colon cancer 2017-07-06 criteria provided, single submitter clinical testing This sequence change affects codon 301 of the PMS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMS2 protein. This variant also falls at the last nucleotide of exon 8 of the PMS2 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant is present in population databases (rs267608153, ExAC 0.003%). This variant has not been reported in the literature in individuals with PMS2-related disease. 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. A different variant at the same nucleotide (c.903G>T) has been reported in six individuals with Lynch syndrome from four families (PMID: 18602922, 26110232). Experimental studies have shown that the c.903G>T change results in skipping of exon 8 and a premature stop codon (p.Tyr268*), indicating that variants at this position likely disrupt mRNA splicing and lead to an absent or truncated protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000573516 SCV000676178 likely pathogenic Hereditary cancer-predisposing syndrome 2016-07-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000614513 SCV000731660 likely pathogenic Lynch syndrome 2017-07-24 criteria provided, single submitter clinical testing The c.903G>A (p.Lys301Lys) variant in PMS2 has not been previously reported in i ndividuals with Lynch syndrome but has been reported in ClinVar by another clini cal laboratory (Variation ID 237932). This variant has also been identified in 2 /111538 European chromosomes by the genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org/; dbSNP rs267608153). Although this silent variant doe s not alter an amino acid residue, it is located in the last base of the exon, w hich is part of the 5? splice region. Computational tools suggest an impact to s plicing; however, this information is not predictive enough to determine pathoge nicity. A different variant at the same nucleotide position (c.903G>T, p.Lys301A sn) has been reported in individuals with Lynch syndrome (Senter 2008, Lavoine 2 015, Suerink 2015). Additionally, in vitro functional splicing studies have show n that the c.903G>T change causes aberrant splicing that leads to skipping of ex on 8 and results in a premature stop codon (van der Klift 2015), suggesting that variants at this position are likely to disrupt RNA splicing. In summary, altho ugh additional studies are required to fully establish its clinical significance , the c.903G>A (p.Lys301Lys) variant is likely pathogenic.

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