ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 pathogenic Hereditary nonpolyposis colon cancer 2019-12-27 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 observed 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), suggesting that this variant (c.2T>C), giving rise to the same protein effect, is also deleterious. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000574743 SCV000670753 pathogenic Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing 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
Color RCV000574743 SCV001351218 pathogenic Hereditary cancer-predisposing syndrome 2020-05-12 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.