ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1A>T (p.Met1Leu) (rs587779333)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132181 SCV000187260 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500454 SCV000592914 pathogenic Lynch syndrome 2015-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000218553 SCV000279131 pathogenic not provided 2017-09-08 criteria provided, single submitter clinical testing PMS2 c.1A>T 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 been reported in a pediatric patient with a personal history of rectal cancer, lymphoma, leukemia, and astrocytoma who also harbored another PMS2 variant and was suspected of having constitutional mismatch repair deficiency (CMMR-D) syndrome (Adam 2016), as well as in an individual with a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). Additionally, a different nucleotide change also resulting in p.Met1?, PMS2 c.1A>G, was reported in a patient with endometrial cancer for which loss of PMS2 protein was observed via immunohistochemistry (Borras 2013). PMS2 c.1A>G was also seen in trans (on opposite chromosomes) with other pathogenic PMS2 variants in at least three individuals with a phenotype suspicious for CMMR-D syndrome and absent PMS2 expression in both tumor and normal tissue (Senter 2008). Based on current evidence, we consider PMS2 c.1A>T to be pathogenic.
Invitae RCV000527509 SCV000625573 pathogenic Hereditary nonpolyposis colon cancer 2018-09-13 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 (rs587779333, ExAC 0.002%). This variant has been reported in an individual suspected of Lynch syndrome (PMID: 25980754), in an individual with a personal history consistent with constitutional mismatch repair deficiency syndrome carrying a second pathogenic PMS2 variant (PMID: 27476653), and in one family affected with breast/ovarian cancer (PMID: 24130102). ClinVar contains an entry for this variant (Variation ID: 142777). Two different variants (c.1A>G and c.2T>A) that also disrupt the PMS2 initiator codon have been reported in individuals with colorectal, endometrial, and breast cancer (PMID: 20487569, 23709753, 25559809, Invitae), and individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMID: 18602922). The two variants have been determined to be pathogenic, suggesting that other substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218553 SCV000889618 pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing

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