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

dbSNP: rs63750250

Total submissions: 29

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	2021-01-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with Lynch syndrome-related cancers and tumor studies consistent with pathogenic variants in this gene (Truninger 2005, Tomsic 2013, Vaughn 2013, Yurgelun 2015, Rosty 2016, van der Klift 2016, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in patients with Constitutional Mismatch Repair Deficiency in the published literature (Alexander 2016, Cheyuo 2017, Hildreth 2018, Oshrine 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1828insA; This variant is associated with the following publications: (PMID: 29625052, 31992580, 31447099, 27037742, 30155321, 31189528, 28562508, 15887099, 25980754, 23012243, 26895986, 27435373, 30322717, 26318770, 26116798, 28874130, 24728327, 28514183, 25512458, 26110232, 26681312, 27017610, 23652311, 24728189, 25691505, 25856668, 22120844, 22577899, 24362816, 20205264, 18602922)
Ambry Genetics	RCV000115666	SCV000172770	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-09	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 mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, many with tumors demonstrating microsatellite instability and/or loss of PMS2 by immunohistochemistry (Truninger K et al. Gastroenterology, 2005 May;128:1160-71; Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Schofield L et al. Fam Cancer, 2012 Mar;11:1-6; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Pagin A et al. Br J Cancer, 2013 May;108:2079-87; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Bodo S et al. Gastroenterology, 2015 Oct;149:1017-29.e3; Susswein LR et al. Genet Med, 2016 08;18:823-32; van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179; Cheyuo C et al. J. Pediatr. Hematol. Oncol., 2017 10;39:e381-e387; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Wang Q et al. J Med Genet, 2020 07;57:487-499; Post CCB et al. J Natl Cancer Inst, 2021 Mar). In addition, this mutation has been identified as homozygous and 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; Shuen AY et al. J Clin Oncol, 2019 02;37:461-470; Perez-Valencia JA et al. Genet Med, 2020 12;22:2081-2088; Oldfield LE et al. J Mol Diagn, 2021 02;23:242-252). This alteration has also been reported in 3/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 1828insA, c.1831_1832insA 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524450	SCV000218784	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	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. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is present in population databases (rs63750250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and constitutional mismatch repair deficiency syndrome and Lynch syndrome or suspected Lynch syndrome and ovarian cancer (PMID: 15887099, 18602922, 20205264, 22577899, 23012243, 24728189, 25512458, 25980754, 26318770). This variant is also known as 1828insA, 1831insA, and 1831_1832insA. ClinVar contains an entry for this variant (Variation ID: 91317). 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 PMS2 c.1831dup (p.Ile611Asnfs*2) variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has been reported in the published literature in several individuals and families affected with colorectal cancer (PMIDs: 15887099 (2005), 25980754 (2015), 27978560 (2016), 30155321 (2018)). The frequency of this variant in the general population, 0.000046 (6/129170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115666	SCV000686165	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000258972	SCV000691965	pathogenic	not provided	2022-08-10	criteria provided, single submitter	clinical testing	PP4, PP5, PM2, PVS1
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, Mass General Brigham 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 (http://gnomad.broadinstitute.org). 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.
St. Jude Molecular Pathology, 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	Lynch syndrome 4	2018-09-13	criteria provided, single submitter	research
Mendelics	RCV000851295	SCV001137285	likely pathogenic	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000258972	SCV001371512	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000258972	SCV002018882	pathogenic	not provided	2021-06-30	criteria provided, single submitter	clinical testing
DASA	RCV000076830	SCV002061241	pathogenic	Lynch syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.1831dup;p.(Ile611Asnfs*2) is a null frameshift variant (NMD) in the PMS2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91317; PMID: 23012243; 25512458; 25980754; 15887099; 18602922; 22577899; 20205264; 24728189) - PS4. This variant is not present in population databases (rs63750250, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Sema4, Sema4	RCV000115666	SCV002530233	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
Daryl Scott Lab, Baylor College of Medicine	RCV000851295	SCV003915713	pathogenic	Lynch syndrome 4	2023-04-11	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000851295	SCV004042794	pathogenic	Lynch syndrome 4	2023-08-03	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4, PM2_SUP
Myriad Genetics, Inc.	RCV000851295	SCV004187675	pathogenic	Lynch syndrome 4	2023-09-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000851295	SCV004205441	pathogenic	Lynch syndrome 4	2024-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076830	SCV004844126	pathogenic	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1828insA, 1831insA and c.1831_1832insA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected by/suspected of having Lynch syndrome (PMID: 18602922, 20205264, 22120844, 24728189, 25512458, 25856668, 26681312), in individuals affected by/suspected of having recessive constitutional DNA mismatch repair deficiency (CMMRD) syndrome (PMID: 26116798, 27017610, 27037742, 28562508, 32773772), and in a compound heterozygous individual affected with invasive adenocarcinoma (PMID: 30155321). This variant has been identified in 6/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PMS2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
ITMI	RCV000121837	SCV000086035	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000144653	SCV000189980	pathogenic	Lynch syndrome 1	2014-07-24	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.
Institute of Human Genetics, Medical University Innsbruck	RCV001254932	SCV001431022	pathogenic	Mismatch repair cancer syndrome 1	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).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000258972	SCV001977681	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000258972	SCV001978562	pathogenic	not provided		no assertion criteria provided	clinical testing