Submissions for variant NM_000535.7(PMS2):c.1939A>T (p.Lys647Ter)

dbSNP: rs201451115

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076836	SCV000108323	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000128864	SCV000172720	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	clinical testing	The p.K647* pathogenic mutation (also known as c.1939A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1939. This changes the amino acid from a lysine to a stop codon within coding exon 11. This mutation has been reported in multiple individuals with Lynch syndrome-associated cancers, several whose tumors demonstrated high microsatellite instability and/or loss of PMS2 staining by immunohistochemistry (Senter L et al. Gastroenterology, 2008 Aug;135:419-28; Vaughn CP et al. Genes Chromosomes Cancer, 2013 Jan;52:107-12; Therkildsen C et al. Eur J Neurol, 2015 Apr;22:717-24; Win AK et al. Fam Cancer, 2015 Dec;14:575-83; Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Norquist BM et al. JAMA Oncol, 2016 Apr;2:482-90; Wang Q et al. J Med Genet, 2020 07;57:487-499). In one case control study, this mutation was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in a patient undergoing multi-gene panel testing for a personal and/or family history of cancer (Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). 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	RCV000627727	SCV000259395	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys647*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 18602922, 23012243, 25856668, 26720728). ClinVar contains an entry for this variant (Variation ID: 91321). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000414304	SCV000490733	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25691505, 25856668, 29922827, 28888541, 18602922, 25648859, 25525159, 26895986, 27153395, 23012243, 31992580, 31447099, 33259954, 26720728, 26202870, 33442023, 30787465, 31345219)
Color Diagnostics, LLC DBA Color Health	RCV000128864	SCV000537649	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with colorectal cancer (PMID: 18602922, 26202870, 25856668, 31992580), and some of these individual's tumors displayed loss of PMS2 protein via immunohistochemistry (IHC) analysis. This variant has also been identified in an individual affected with ovarian serous carcinoma (PMID: 26720728) and an individual with an unspecified cancer (PMID: 23012243). This variant has been identified in 1/250882 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507921	SCV000604888	pathogenic	not specified	2017-06-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000414304	SCV000609841	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000414304	SCV000806192	pathogenic	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709754	SCV000840048	pathogenic	Lynch syndrome 4	2017-09-19	criteria provided, single submitter	clinical testing	This c.1939A>T (p.Lys647*) variant in the PMS2 gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with Lynch syndrome or colorectal cancer (PMID: 18602922, 25856668, 23012243). The c.1939A>T (p.Lys647*) variant in the PMS2 gene is classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000709754	SCV000993577	pathogenic	Lynch syndrome 4	2018-07-11	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000414304	SCV001247257	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PMS2: PVS1, PM2, PS4:Moderate
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000414304	SCV001450440	pathogenic	not provided	2019-11-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000414304	SCV001469859	pathogenic	not provided	2020-01-02	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228187	SCV002511547	pathogenic	Hereditary nonpolyposis colon cancer	2022-04-19	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1939A>T (p.Lys647X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250882 control chromosomes. c.1939A>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (example, Senter_2008, Therkildsen_2014, Espenschied_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000128864	SCV002530243	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	curation
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000507921	SCV002578154	pathogenic	not specified	2022-09-27	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288575	SCV002579290	pathogenic	Mismatch repair cancer syndrome 4	2021-06-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709754	SCV003921068	pathogenic	Lynch syndrome 4	2024-03-21	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM2_SUP, PP4_SUP
Myriad Genetics, Inc.	RCV000709754	SCV004187677	pathogenic	Lynch syndrome 4	2023-09-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000709754	SCV004207806	pathogenic	Lynch syndrome 4	2023-06-18	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV000709754	SCV004704550	pathogenic	Lynch syndrome 4	2023-11-21	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PS4, PM2_SUP
All of Us Research Program, National Institutes of Health	RCV000076836	SCV004844114	pathogenic	Lynch syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with colorectal cancer (PMID: 18602922, 26202870, 25856668, 31992580), and some of these individual's tumors displayed loss of PMS2 protein via immunohistochemistry (IHC) analysis. This variant has also been identified in an individual affected with ovarian serous carcinoma (PMID: 26720728) and an individual with an unspecified cancer (PMID: 23012243). This variant has been identified in 1/250882 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076836	SCV004847688	pathogenic	Lynch syndrome	2019-04-02	criteria provided, single submitter	clinical testing	The p.Lys647X variant in PMS2 has been reported in at least 5 individuals with PMS2-related cancers (Senter 2008, Win 2015, Norquist 2016, Goodenberger 2016). It has also been identified in 1/113618 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 647, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal autosomal dominant Lynch syndrome. In addition, this variant was classified as Pathogenic on Sept 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID: 91321). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.