Submissions for variant NM_000535.7(PMS2):c.697C>T (p.Gln233Ter)

dbSNP: rs587779343

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076881	SCV000108375	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000212848	SCV000149610	pathogenic	not provided	2018-06-14	criteria provided, single submitter	clinical testing	This variant is denoted PMS2 c.697C>T at the cDNA level and p.Gln233Ter (Q233X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with a personal and/or family history consistent with Lynch syndrome (Niessen 2009, van der Klift 2016, Rossi 2017) and is considered pathogenic.
Ambry Genetics	RCV000115701	SCV000214344	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	clinical testing	The p.Q233* pathogenic mutation (also known as c.697C>T), located in coding exon 6 of the PMS2 gene, results from a C to T substitution at nucleotide position 697. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This alteration was first reported in an individual with a uterine sarcoma diagnosed at 52 years and colorectal carcinoma (exhibiting microsatellite instability) diagnosed at 62 and 63 years (Niessen RC et al. Genes Chromosomes Cancer 2009 Apr;48:322-9). It has since been reported in multiple families with Lynch syndrome associated cancers (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33:319-25; van der Klift HM et al. Hum. Mutat. 2016 11;37(11):1162-1179; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623). Furthermore, this alteration has been shown to result in nonsense mediated mRNA decay by RT-PCR (van der Klift HM et al. Hum. Mutat. 2010 May;31:578-87). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	RCV000524479	SCV000551989	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-11	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs587779343, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 91362). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and suspected Lynch syndrome (PMID: 19132747, 20186688, 25512458, 26110232, 27435373). This sequence change creates a premature translational stop signal (p.Gln233*) 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).
Color Diagnostics, LLC DBA Color Health	RCV000115701	SCV000686226	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the PMS2 gene, creating a premature translation stop signal. 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 with Lynch syndrome (PMID: 16472587, 19132747, 25512458, 26110232, 27435373, 28874130) and breast/ovarian cancer (PMID: 27153395, 29345684, 33471991; DOI: 10.1101/2021.04.15.21255554). This variant has been identified in 3/282860 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	RCV000076881	SCV000697377	pathogenic	Lynch syndrome	2017-05-05	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.697C>T (p.Gln233X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.735dupG [p.Pro246fsX3], c.823C>T [p.Gln275X], and c.1021delA [p.Arg341fsX15]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000082 (1/121462 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In the literature, patients and families with colorectal cancer and other Lynch syndrome-associated cancers have been identified as carriers of the variant and include supporting molecular data, such as absence of PMS2 in tumor samples (via immunohistochemical staining) and microsatellite instability (Niessen_GCC_2009; van der Klift_HM_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001799617	SCV002044438	pathogenic	Lynch syndrome 4	2021-12-10	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4
DASA	RCV000076881	SCV002498792	pathogenic	Lynch syndrome	2022-04-10	criteria provided, single submitter	clinical testing	The c.697C>T;p.(Gln233*) variant creates a premature translational stop signal in the PMS2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 91362; PMID: 19132747; PMID: 20186688; PMID: 27435373) - PS4. The variant is present at low allele frequencies population databases (rs587779343 – gnomAD 0.0001061%; ABraOM no frequency - http://abraom.ib.usp.br) - PM2_supporting. The variant was identified in an individual with a highly specific phenotype for the condition (PMID: 19132747, 27435373) - PP4. In summary, the currently available evidence indicates that the variant is pathogenic
Revvity Omics, Revvity	RCV000212848	SCV003818379	pathogenic	not provided	2022-09-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001799617	SCV004183389	pathogenic	Lynch syndrome 4	2019-12-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2
Myriad Genetics, Inc.	RCV001799617	SCV004187729	pathogenic	Lynch syndrome 4	2023-09-19	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	RCV001799617	SCV004203412	pathogenic	Lynch syndrome 4	2021-11-29	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212848	SCV001739709	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212848	SCV001905895	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212848	SCV001957201	pathogenic	not provided		no assertion criteria provided	clinical testing