ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2T>C (p.Met1Thr) (rs587780059)

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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 RCV000574743 SCV000670753 pathogenic Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Counsyl RCV000662846 SCV000785712 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-11-08 criteria provided, single submitter clinical testing
GeneDx RCV000115692 SCV000149601 pathogenic not provided 2016-01-20 criteria provided, single submitter clinical testing PMS2 c.2T>C results in the loss of the initiator Methionine codon, and the resultant protein would be described as p.Met1?" to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, the adjacent variant c.1A>G, which also results in p.Met1?, has been reported in a patient with endometrial cancer for which loss of PMS2 protein was observed via immunohistochemistry, as well as in trans (on opposite chromosomes) with other pathogenic PMS2 variants in at least three individuals with a phenotype suspicious for constitutional mismatch repair deficiency syndrome and absent PMS2 expression in both tumor and normal tissues (Senter 2008, Borras 2013). Based on current evidence, we consider PMS2 c.2T>C to be pathogenic."
Invitae RCV000461697 SCV000552076 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-29 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PMS2 mRNA. The nearest in-frame methionine that could be used to initiate PMS2 translation occurs at codon 136, and therefore this variant is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780059, ExAC 0.002%). This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 26898890, 26681312). ClinVar contains an entry for this variant (Variation ID: 127788). Different nucleotide changes (c.1A>G, c.2T>A) at the initiator codon have been reported in individuals with colorectal and endometrial cancer (PMID: 20487569, 23709753, 25559809), and in individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome, who also carried a second pathogenic PMS2 variant (PMID: 18602922, 27476653). The c.1A>G and c.2T>A variants have been classified as pathogenic (Invitae database), suggesting that this variant (c.2T>C), giving rise to the same protein effect, is also deleterious. In summary, this is a rare variant that disrupts the PMS2 translation initiation codon. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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