Submissions for variant NM_000535.7(PMS2):c.823C>T (p.Gln275Ter)

dbSNP: rs587780062

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115704	SCV000149613	pathogenic	not provided	2022-08-05	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; This variant is associated with the following publications: (PMID: 24689082, 26681312, 28514183, 26110232, 23012243, 25512458, 31992580, 31447099, 30787465, 33087929, 22848017)
Ambry Genetics	RCV000216292	SCV000276072	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-11	criteria provided, single submitter	clinical testing	The p.Q275* pathogenic mutation (also known as c.823C>T), located in coding exon 8 of the PMS2 gene, results from a C to T substitution at nucleotide position 823. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This mutation has been reported in two Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome families in the Netherlands (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb;33(4):319-25); in a child diagnosed with constitutional mismatch repair deficiency (CMMR-D) who also had a second PMS2 mutation (Yeung JT et al. Pediatr Blood Cancer. 2013 Jan;60(1):137-9); and in a patient with endometrial cancer (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). 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	RCV000552808	SCV000625695	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln275*) 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 (rs587780062, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, and constitutional mismatch repair deficiency (PMID: 23012243, 24689082, 26110232). ClinVar contains an entry for this variant (Variation ID: 127796). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709755	SCV000840050	pathogenic	Lynch syndrome 4	2017-11-26	criteria provided, single submitter	clinical testing	This c.823C>T (p.Gln275*) variant in the PMS2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with cancer (PMID: 22848017, 25512458, 24689082, 26681312). The c.823C>T (p.Gln275*) variant in the PMS2 gene is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763589	SCV000894428	pathogenic	Mismatch repair cancer syndrome 1; Lynch syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216292	SCV000905475	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 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 an individual affected with constitutional mismatch mismatch repair deficiency who also carried another pathogenic PMS2 variant in trans (PMID: 22848017), as well as in multiple individuals affected with Lynch syndrome (PMID: 25512458, 27435373, 31992580). This variant has been identified in 2/251410 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	RCV001264438	SCV001442589	pathogenic	Hereditary nonpolyposis colon cancer	2020-10-28	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.823C>T (p.Gln275X) 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 8e-06 in 251410 control chromosomes (gnomAD). c.823C>T has been reported in the literature in multiple individuals affected with colorectal cancer and Lynch syndrome (Yeung_2013, Hansen_2014, ten Broeke_2015, van der Klift_2016, Wang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000709755	SCV001736885	pathogenic	Lynch syndrome 4	2021-04-26	criteria provided, single submitter	research	ACMG codes:PVS1; PS4M; PM2; PP5
Revvity Omics, Revvity	RCV000115704	SCV002019436	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000709755	SCV002579973	pathogenic	Lynch syndrome 4	2022-05-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000709755	SCV004187662	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	RCV000709755	SCV004205359	pathogenic	Lynch syndrome 4	2023-10-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115704	SCV004219028	pathogenic	not provided	2022-12-18	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. The frequency of this variant in the general population, 0.000008 (2/251410 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 31992580 (2020), 25512458 (2015), 23012243 (2013)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997292	SCV004839908	pathogenic	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	The c.823C>T (p.Gln275*) variant in the PMS2 gene is located on the exon 8 and introduces a premature translation termination codon (p.Gln275*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancer or constitutional mismatch repair-deficiency syndrome (PMID: 28514183, 24689082, 27435373, 26110232, 23012243, 22848017). Loss-of-function variants in PMS2 are known to be pathogenic and variants located downstream to this position in this exon have been reported as pathogenic (PMID: 28514183, 25512458, 35223509, p.Gln288fs, ClinVar ID: 91376). The variant is reported in ClinVar (ID: 127796). The variant is rare in the general population according to gnomAD (2/251410). Therefore, the c.823C>T (p.Gln275*) variant of PMS2 has been classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003997292	SCV004848310	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Gln275X variant in PMS2 has been reported in at least 4 heterozygous individuals with PMS2-associated cancers and in 1 compound heterozygous individual with constitutive mismatch repair deficiency (Espenschied 2017, Susswein 2016, Suerink 2016, Hansen 2014, Vaughn 2013, Yeung 2013). This variant has been identified in 2/34590 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (pathogenic by several clinical labs (ClinVar ID 127796). This nonsense variant leads to a premature termination codon at position 275, 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 dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000709755	SCV005402237	pathogenic	Lynch syndrome 4	2024-06-23	criteria provided, single submitter	clinical testing	The PMS2 c.823C>T (p.Gln275Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with Lynch-syndrome associated cancers (PMID: 27435373, 31992580). This variant has also been reported in conjunction with another pathogenic variant in an individual with constitutional mismatch repair deficiency (PMID: 22848017). This variant has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005042216	SCV005674339	pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2024-04-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000115704	SCV001739539	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000115704	SCV001951717	pathogenic	not provided		no assertion criteria provided	clinical testing