ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2T>G (p.Met1Arg) (rs587780059)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219633 SCV000275852 pathogenic Hereditary cancer-predisposing syndrome 2015-05-21 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion)
Invitae RCV000458145 SCV000552058 pathogenic Hereditary nonpolyposis colon cancer 2018-12-27 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 not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231873). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant (c.1A>G), giving rise to the same protein effect which disrupts the initiator codon, has been reported in individuals affected with colorectal cancer (PMID: 20487569), endometrial cancer (PMID: 23709753) and in several individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922), indicating that this residue may be critical for protein function. Two different variants (c.1A>T and c.2T>A) that also disrupt the PMS2 initiator codon have been reported in an individual with a history of Lynch Syndrome associated cancer and/or colorectal polyps (PMID: 25980754) and in an individual with breast cancer and multiple myeloma (Invitae database), supporting the notion that this initiator codon is critical for PMS2 translation. For these reasons, this variant has been classified as Pathogenic.

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