ClinVar Miner

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

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Total submissions: 21
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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 The c.1831dupA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of A at nucleotide position 1831, causing a translational frameshift with a predicted alternate stop codon (p.I611Nfs*2). This alteration has been previously reported in multiple colorectal cancer patients whose tumors demonstrated absence of PMS2 staining by IHC (Truninger K et al. Gastroenterology. 2005 May;128:1160-71; Senter L et al. Gastroenterology. 2008 Aug;135:419-28). In one case control study, this alteration was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). In addition, this mutation has been identified in trans with additional PMS2 alterations in patients with constitutional mismatch repair deficiency (CMMRD) phenotypes (Lavoine N et al. J. Med. Genet. 2015 Nov;52:770-8; Alexander TB et al. Pediatr. Blood Cancer. 2016 Aug;63:1454-6; Mork ME et al. Fam. Cancer. 2016 Oct;15:587-91; Hildreth A et al. Case Rep. Genet. 2018 Jul;2018:8657823). Of note, this alteration is also designated as 1828insA and 1831dup in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000524450 SCV000218784 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-19 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 2020-05-29 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Color Health, Inc RCV000115666 SCV000686165 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2019-04-19 criteria provided, single submitter clinical testing The p.Ile611AsnfsX2 variant in PMS2 has been reported in 12 individuals with colorectal cancer including 10 with Lynch Syndrome (Bodo 2015, ten Broeke 2015, Lavoine 2015, Goodenberger 2016, Susswein 2016), as well as in compound heterozygosity with another PMS2 variant in 2 individuals and 1 family member with constitutional MMR deficiency (Lavoine 2015, Bodo 2015, Susswein 2016). The p.Ile611AsnfsX2 variant has also been identified in 6/129170 of European chromosomes by gnomAD ( In addition, it has been classified as Pathogenic on September 5, 2013 by the InSiGHT expert panel (ClinVar SCV000108317.2). This 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. Heterozygous loss of function of function of the PMS2 gene is an established disease mechanism in colorectal cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PM2,PS4_Moderate, PM3_Supporting, PVS1.
Mendelics RCV000076830 SCV000838174 likely pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000076830 SCV000853184 pathogenic Lynch syndrome 2020-09-30 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.
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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000258972 SCV001371512 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
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 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.
Division of Human Genetics,Medical University Innsbruck RCV001254932 SCV001431022 pathogenic Turcot syndrome 2020-05-06 no assertion criteria provided research This variant, NM_000535.6:c.1831dupA, was found in compound heterozygosity with the pathogenic variant NM_000535.6:c.(988+1_989-1)_(1144+1_1145-1)del. Sample UAB117 in Perez J et al, Genet Med (PMID: 32773772).

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