Submissions for variant NM_000535.7(PMS2):c.1882C>T (p.Arg628Ter)

gnomAD frequency: 0.00002  dbSNP: rs63750451

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076834	SCV000108321	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000218575	SCV000277667	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-17	criteria provided, single submitter	clinical testing	The p.R628* pathogenic mutation (also known as c.1882C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1882. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been reported in several unrelated hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome patients and families; several with tumors demonstrating loss of PMS2 by immunohistochemistry (IHC) (Hendriks YM et al. Gastroenterology, 2006 Feb;130:312-22; van der Klift HM et al. Hum Mutat, 2010 May;31:578-87; Suerink M et al. Genet Med, 2016 Apr;18:405-9; Sugano K et al. Cancer Sci, 2016 Nov;107:1677-1686; Post CCB et al. J Natl Cancer Inst, 2021 Sep;113:1212-1220). This mutation has also been identified in two individuals with breast cancer undergoing multi-gene panel testing (Roberts ME et al. Genet. Med. 2018 10;20:1167-1174). 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.
GeneDx	RCV000220439	SCV000279234	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	Observed in individuals with PMS2-related cancers, including those with tumor studies consistent with pathogenic variants in this gene (Hendriks et al., 2006; van Puijenbroek et al., 2008; ten Broeke et al., 2015; Suerink et al., 2016; Sugano et al., 2016); 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: 25980754, 20186688, 26110232, 30217226, 28888541, 29758216, 34697415, 25512458, 16472587, 18415027, 25691505, 27589204, 27435373, 28600700, 19283792, 25525159, 30787465, 29625052)
Invitae	RCV000524451	SCV000551972	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg628*) 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 (rs63750451, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency syndrome and Lynch syndrome (PMID: 16472587, 19283792, 25512458, 26110232, 27435373, 27589204). ClinVar contains an entry for this variant (Variation ID: 9242). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009823	SCV000745188	pathogenic	Lynch syndrome 4	2016-03-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218575	SCV000905473	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-27	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 or endometrial cancer that exhibited microsatellite instability and loss of PMS2 proteins by immunohistochemistry analyses (PMID: 16472587, 18415027, 27589204, 34253388, 36931573). This variant has also been reported in individuals affected with breast cancer (PMID: 16472587, 29345684). This variant has been identified in 4/251434 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193819	SCV001362953	pathogenic	Hereditary nonpolyposis colon cancer	2019-06-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1882C>T (p.Arg628X) 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. RT-PCR analysis on RNA derived from cultured lymphocytes of patients carrying the variant demonstrated nonsense-mediated RNA decay (van der Klift_2010, 2016). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes (gnomAD). c.1882C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Hendriks_2006, Sugano_2016, van der Klift_2010, 2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000220439	SCV002019439	pathogenic	not provided	2021-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000218575	SCV002530238	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000009823	SCV004187756	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	RCV000009823	SCV004205394	pathogenic	Lynch syndrome 4	2023-10-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000220439	SCV004218966	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	This variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 27589204 (2016), 27435373 (2016), 16472587 (2006)), breast cancer (PMID: 29345684 (2018)), ovarian/endometrial cancer (PMIDs: 29625052 (2018), 28888541 (2017)), and CMMRD (PMID: 27435373 (2016)). RNA analysis indicated the variant mRNA transcript is subjected to nonsense-mediated decay (PMID: 20186688 (2010)). The frequency of this variant in the general population, 0.000016 (4/251434 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000009823	SCV000030044	pathogenic	Lynch syndrome 4	2006-02-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000009823	SCV000734561	pathogenic	Lynch syndrome 4		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000220439	SCV001958890	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000220439	SCV002035944	pathogenic	not provided		no assertion criteria provided	clinical testing