ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1A>G (p.Met1Val) (rs587779333)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160894 SCV000885991 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564071 SCV000663423 pathogenic Hereditary cancer-predisposing syndrome 2017-03-31 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),Significant disease association in appropriately sized case-control study(ies),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Color RCV000564071 SCV000691053 pathogenic Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing
Counsyl RCV000410400 SCV000488365 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000160894 SCV000211586 pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing The c.1A>G variant in the PMS2 gene alters 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 history of endometrial cancer for which loss of PMS2 protein was observed via mismatch repair immunohistochemistry (Borras 2013). PMS2 c.1A>G has also been observed in trans (on opposite chromosomes) with known pathogenic variants in PMS2 in at least three individuals with a phenotype consistent with constitutional mismatch repair deficiency syndrome; loss of PMS2 protein was observed in both tumor and normal surrounding tissue (Senter 2008). We therefore consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076838 SCV000697323 likely pathogenic Lynch syndrome 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide that results with the alteration of the translational start site. The nearest in-frame alternate methionine residue that could be used to initiate PMS2 translation occurs at codon 136, therefore this variant is expected to result in an absent or disrupted protein product, although these findings have not been confirmed by functional studies. 3/5 in silico tools predict a benign outcome. The variant of interest was observed in controls obtained from the Tomsic_2013 paper that performed long-range PCR analysis to eliminate the possibility of the pseudogene and was found to have an allele frequency of 0.04375, which does exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). Multiple publications have cited the variant in affected individuals including a family with an unaffected individual carrying the variant (Borras_2013). Additionally, publications and clinical labs cite affected individuals who carry another potentially pathogenic PMS2 variant in trans such as deletion of exons 9 and 10, c.251-2A>G (Senter_2008) and a patient who is homozygous for the variant (Ambry Genetics). Individuals from the Senter_2008 publication also showed loss of PMS2 expression. Carrying two MMR mutations in the same gene in trans has been associated with constitutional mismatch repair-deficiency, which is characterized by colonic polyposis and hematologic, brain and gastrointestinal malignancies, as well as neurofribromas, which present at a young age and thus both mutations may be explaining the phenotype in the individuals reported. Additionally, another alteration at this position, c.1A>T (p.Met1Leu) has been classified as likely pathogenic by LCA, although the variant was only observed once in controls. Furthermore, multiple clinical diagnostic laboratories in ClinVar have classified this variant as Pathogenic/Likely Pathogenic and one lab has classified it as a variant of uncertain clinical significance. Therefore, until additional evidence becomes available, particularly functional evidence, the variant of interest has been classified as a Likely Pathogenic variant.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000144649 SCV000108326 likely pathogenic Lynch syndrome I 2017-06-30 reviewed by expert panel curation meets criteria for Class 4
Invitae RCV000524456 SCV000166382 pathogenic Hereditary nonpolyposis colon cancer 2018-12-17 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, 0.01%). This variant has been reported in individuals affected with colorectal cancer (PMID: 20487569) and endometrial cancer (PMID: 23709753), and several individuals with a personal history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922). In addition to the c.1A>G variant, each individual carried a second PMS2 variant that is likely pathogenic, and immunohistochemistry results from the tumors of these individuals showed absence of PMS2 expression (PMID: 18602922). ClinVar contains an entry for this variant (Variation ID: 91323). 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 an individual with breast cancer and multiple myeloma (Invitae), suggesting that this initiator codon is critical for PMS2 translation. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000076838 SCV000711436 likely pathogenic Lynch syndrome 2019-01-31 criteria provided, single submitter clinical testing The c.1A>G variant in PMS2 has been reported in the heterozygous state at least 2 individuals with Lynch syndrome-associated cancers and 1 individual who was re ferred for clinical genetic testing of germline cancer genes (Talseth-Palmer 201 0, Borras 2013, Susswein 2015). It has also been also reported in the compound h eterozygous state in at least 3 individuals with constitutional mismatch repair deficiency (CMMRD; Senter 2008, LOVD database). Additionally, the c.1A>G variant has been identified in 4/125936 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587779333). This var iant affects the translation initiation start codon (ATG) and is therefore predi cted to disrupt translation. The precise effect on the protein cannot be predict ed, as this variant may lead to no protein synthesis or the activation of an ups tream translation initiation codon, resulting in an aberrant protein. Heterozygo us loss of function of the PMS2 gene is an established disease mechanism in Lync h Syndrome. However, this exon is not present on all PMS2 transcripts. Moreover , this variant has been classified as likely pathogenic on June 30, 2017 by the ClinGen-approved InSiGHT Expert Panel (ClinVar SCV000108326.2). In summary, whil e additional studies are required to fully establish its clinical significance, the c.1A>G variant is likely pathogenic.
Pathway Genomics RCV000144649 SCV000189976 likely pathogenic Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160894 SCV000601834 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing

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