ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.904-2A>G (rs587781339)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129110 SCV000183822 pathogenic Hereditary cancer-predisposing syndrome 2016-09-08 criteria provided, single submitter clinical testing The c.904-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the PMS2 gene. This variant was reported in a patient who had right colorectal cancer at age 48, prostate cancer at age 68, and a numerous polyps (Selkirk CG et al. Fam. Cancer. 2014 Dec;13(4):527-36). In addition to the clinical data presented in the literature, 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 pathogenic.
Invitae RCV000206112 SCV000261727 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features consistent with Lynch syndrome (PMID: 25117502, 27696107). Donor and acceptor splice site variants 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). 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.
Counsyl RCV000576592 SCV000677800 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129110 SCV000686254 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-28 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the PMS2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. 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 been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 24763289, 25117502, 27696107, 28514183). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Likely Pathogenic.

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