ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.537+1del

dbSNP: rs1064793868
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485795 SCV000567235 pathogenic not provided 2015-07-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.537+1delG or IVS5+1delG and consists of a single nucleotide deletion at the +1 position of intron 5 of the PMS2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-medicated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV001223326 SCV001395468 pathogenic Hereditary nonpolyposis colorectal neoplasms 2023-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu180Serfs*21) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). 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. This variant is also known as c.537+1del. ClinVar contains an entry for this variant (Variation ID: 419435). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000758169 SCV002646454 pathogenic Hereditary cancer-predisposing syndrome 2021-12-23 criteria provided, single submitter clinical testing The c.537+1delG intronic pathogenic mutation, located in intron 5 of the PMS2 gene, results from a deletion of one nucleotide within intron 5 of the PMS2 gene. This alteration has been observed in an individual diagnosed with colorectal cancer exhibiting loss of PMS2 protein by immunohistochemistry in their 40s (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002506164 SCV002813821 likely pathogenic Lynch syndrome 4; Mismatch repair cancer syndrome 4 2021-11-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003449191 SCV004187642 likely pathogenic Lynch syndrome 4 2023-09-19 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics RCV003449191 SCV004205406 likely pathogenic Lynch syndrome 4 2023-10-06 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000758169 SCV000886701 pathogenic Hereditary cancer-predisposing syndrome 2018-10-03 no assertion criteria provided clinical testing

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