ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1831dup (p.Ile611fs) (rs63750250)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076830 SCV000108317 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000258972 SCV000149575 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing This duplication of one nucleotide in PMS2 is denoted c.1831dupA at the cDNA level and p.Ile611AsnfsX2 (I611NfsX2) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAAA[dupA]TTAA. The duplication causes a frameshift which changes an Isoleucine to an Asparagine at codon 611, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.1831dupA, also known as 1828insA, is a recurrent variant associated with Lynch syndrome (Truninger 2005, Tomsic 2013, Rosty 2016, van der Klift 2016) and has been observed in trans with a pathogenic PMS2 variant in at least one individual with constitutional mismatch repair deficiency (Alexander 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000115666 SCV000172770 pathogenic Hereditary cancer-predisposing syndrome 2018-08-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000524450 SCV000218784 pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile611Asnfs*2) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63750250, ExAC 0.001%). This variant has been reported in individuals and families affected with Lynch syndrome or suspected Lynch syndrome (PMID: 23012243, 25512458, 25980754), individuals affected with colorectal cancer (PMID: 15887099, 18602922, 22577899, 20205264), an individual affected with ovarian cancer (PMID: 24728189), and an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA in the literature. ClinVar contains an entry for this variant (Variation ID: 91317). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076830 SCV000592940 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000258972 SCV000601829 pathogenic not provided 2015-07-09 criteria provided, single submitter clinical testing
Color RCV000115666 SCV000686165 pathogenic Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076830 SCV000697314 pathogenic Lynch syndrome 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1831dupA (p.Ile611Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant was found in 1/121354 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in several cancer patients whose tumor had high MSI and lack of PMS2 staining based on IHC indicating pathogenicity. Additionally, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln637fs) suggesting the clinical importance of the C-termial region located downstream of the variant. Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000076830 SCV000711443 pathogenic Lynch syndrome 2016-11-16 criteria provided, single submitter clinical testing The p.Ile611fs variant in PMS2 has been reported in 12 individuals with colorect al cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity w ith another PMS2 variant in 2 individuals and 1 family member with constitutiona l MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611fs varian t has also been identified in 1/66728 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750250). In a ddition, it has been classified as Pathogenic on September 5, 2013 by the InSiGH T expert panel (ClinVar SCV000108317.2). The p.Ile611fs variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 611 and leads to a premature termination codon 2 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. He terozygous loss of function of function of the PMS2 gene is an established disea se mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for colorectal cancer.
Mendelics RCV000076830 SCV000838174 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722011 SCV000853184 pathogenic Burkitt lymphoma; Lymphoma 2017-03-07 criteria provided, single submitter clinical testing This is a frameshift alteration in which coding nucleotide 1831 is duplicated. This is predicted to change an Isoleucine to an Aparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids downstream. Classification crieria: PVS1, PS3, PM2.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722015 SCV000853188 pathogenic Acute lymphoid leukemia; Glioblastoma 2017-05-11 criteria provided, single submitter clinical testing This is a frameshift alteration in which an A is duplicated at coding nucleotide 1831 and is predicted to change an Isoleucine to an Asparagine at amino acid codon 611, shift the reading frame and result in a premature stop codon 2 amino acids down stream. Classification criteria: PVS1, PS3, PM2.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851295 SCV000993578 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2018-09-13 criteria provided, single submitter research
Mendelics RCV000851295 SCV001137285 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000121837 SCV001159704 pathogenic not specified 2019-01-29 criteria provided, single submitter clinical testing The PMS2 c.1831dupA; p.Ile611fs variant (rs63750250), also known as 1828insA, is reported in several individuals and families with colorectal cancer/Lynch syndrome, and in individuals with constitutional mismatch repair deficiency when found in trans with an additional pathogenic PMS2 variant (Hildreth 2018, Lavoine 2015, Mork 2016, Rossi 2017, Truninger 2005). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 91317). It is found in the general population with an overall allele frequency of 0.002% (6/282838 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Hildreth A et al. Biallelic Mismatch Repair Deficiency in an Adolescent Female. Case Rep Genet. 2018 Jul 25;2018:8657823. Lavoine N et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015 Nov;52(11):770-8. Mork ME et al. Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency. Fam Cancer. 2016 Oct;15(4):587-91. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Truninger K et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005 May;128(5):1160-71.
ITMI RCV000121837 SCV000086035 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144653 SCV000189980 pathogenic Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000258972 SCV000691965 pathogenic not provided no assertion criteria provided clinical testing
True Health Diagnostics RCV000115666 SCV000788111 pathogenic Hereditary cancer-predisposing syndrome 2017-10-16 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000076830 SCV000840125 not provided Lynch syndrome no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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