ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2T>A (p.Met1Lys) (rs587780059)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160895 SCV000214325 pathogenic Hereditary cancer-predisposing syndrome 2017-11-01 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,Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000160895 SCV000691064 pathogenic Hereditary cancer-predisposing syndrome 2016-08-02 criteria provided, single submitter clinical testing
Counsyl RCV000500749 SCV000785677 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-10-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763593 SCV000894432 pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212834 SCV000211587 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing PMS2 c.2T>A 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 an individual with a personal and family history of colorectal cancer (Chubb 2015) as well as in the compound heterozygous state in an individual with constitutional mismatch repair deficiency syndrome and absent PMS2 expression in tumor and normal tissues (Adam 2016). In addition, 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>A to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000500749 SCV000596477 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781734 SCV000920019 pathogenic Lynch syndrome 2018-01-29 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 245322 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Lynch Syndrome (8.2e-06 vs 0.00011), allowing no conclusion about variant significance. c.2T>A has been reported in the literature in individuals affected with CRC and CMMRD (Chubb_2015, Adam_2016, and Susswein_2016). Among them, one patient carried biallelic PMS2 mutation (variant of interest and c.863delA/p.Gln288Argfs*19), IHC staining showed complete loss of PMS2 in both tumor and normal tissue (Adam_2016). Moreover, Ambry genetics reported three occurrences of this variant (Espenschied_ 2017). Haraldsdottir_2017 reported variant associated with a significantly increased risk of endometrial, colorectal and ovarian cancer, although the overall cancer risks are lower than for the MSH6 mutation among Icelanders. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Variants involving the same codon (such as M1L, M1T, and M1V) have been reported in affected individuals suggesting the functional importance of this position. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000229181 SCV000285128 pathogenic Hereditary nonpolyposis colon cancer 2018-12-10 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the PMS2 mRNA. The next in-frame methionine is located at codon 136. This variant is present in population databases (rs587780059, ExAC 0.003%). This variant has been reported in individuals with colorectal cancer (PMID: 25559809) and breast and/or ovarian cancer (PMID: 26898890), as well as in an individual with constitutional mismatch-repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMID: 27476653). ClinVar contains an entry for this variant (Variation ID: 182809). This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 136, this would result in the partial disruption of the ATPase domain, which is important for the mismatch repair activity of the PMS2 protein (PMID: 11574484, 11897781). However, functional studies have not been published for this variant. A different change (c.1A>G) at the initiator codon has been reported in individuals with colorectal and endometrial cancer (PMID: 20487569, 23709753), and individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome who also carried a second pathogenic PMS2 variant (PMID: 18602922). The c.1A>G variant has been determined to be pathogenic, suggesting that other substitutions at this position may also be pathogenic. For these reason, this variant has been classified as Pathogenic.

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