ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.988+1G>T

dbSNP: rs757110564
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001243900 SCV001417087 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-09-23 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 968704). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs757110564, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 9 of the PMS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816).
Color Diagnostics, LLC DBA Color Health RCV001524006 SCV001733761 likely pathogenic Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the canonical +1 position of intron 9 splice donor of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing and cause out-of-frame skipping of exon 9. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/250960 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics RCV001524006 SCV002693241 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing The c.988+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 9 of the PMS2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic.
Myriad Genetics, Inc. RCV003449767 SCV004187617 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.

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