Submissions for variant NM_000535.7(PMS2):c.1687C>T (p.Arg563Ter)

dbSNP: rs587778618

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132169	SCV000187247	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The p.R563* pathogenic mutation (also known as c.1687C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration has been detected in an individual diagnosed with a brain tumor at the age of 8 and an NF1 phenotype who was also identified to carry a PMS2 exon 15 deletion (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93; Vaughn CP et al. Hum Mutat, 2011 Sep;32:1063-71). This mutation has also been detected in trans with a gross PMS2 deletion involving exons 12 through 14 in a 13 year-old patient diagnosed with rectal cancer and two cafe-au-lait spots, a phenotype consistent with CMMR-D (Vasovcak P et al. DNA Repair (Amst.). 2012 Jul;11:616-23). This alteration was also reported in the homozygous state in a pediatric patient with a personal history of AML and osteosarcoma (Ortiz MV et al. Pediatr Blood Cancer, 2016 08;63:1368-74). Additionally, this alteration has been reported in several individuals with early onset colorectal cancer whose tumors demonstrated absent PMS2 protein staining on immunohistochemistry (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Wang Q et al. J Med Genet, 2020 07;57:487-499). 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	RCV000222921	SCV000279143	pathogenic	not provided	2021-01-27	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and in a child with personal history suspicious for CMMR-D without a second identifiable PMS2 pathogenic variant (Vaughn 2010, Goodenberger 2016, AlDubayan 2018, Wang 2020); Observed with a pathogenic variant on the opposite allele (in trans) and in the apparent homozygous state in individuals with personal histories consistent with Constitutional Mismatch Repair Deficiency in the published literature (Vasovcak 2012, Ortiz 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 28502729, 29625052, 26689913, 24728327, 25525159, 20205264, 26648449, 27742654, 28281021, 29478780, 30217226, 25856668, 27082517, 22608206, 31992580, 31512090, 31650731, 31857677, 30787465)
Invitae	RCV000530464	SCV000625550	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg563*) 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 (rs587778618, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with colorectal cancer, breast cancer and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 20205264, 22608206, 25856668). ClinVar contains an entry for this variant (Variation ID: 135067). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132169	SCV000686154	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	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 individuals affected with Lynch syndrome (PMID: 31992580), breast and/or ovarian cancer (31512090, 31650731), and colorectal cancer (PMID: 25856668, 29478780, 31857677). This variant has also been reported in compound heterozygous individuals affected with constitutional mismatch repair deficiency (PMID: 21618646, 22608206). This variant has been identified in 2/251330 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222921	SCV000888400	pathogenic	not provided	2020-09-14	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. In the published literature, this variant has been reported in individuals with lynch syndrome whose tumors showed loss of PMS protein in Immunohistochemistry assays (PMID: 31992580 (2020)). In addition, this variant has been detected in individuals affected with other cancers including colorectal, breast and/or ovarian, endometrial, kidney and brain cancers (PMIDs: 31857677 (2020), 31650731 (2020), 31512090 (2019), 31336956 (2019), 30103829 (2018), 29478780 (2018), 27376475 (2016), 25194673 (2014), and 20205264 (2010). Also, this variant has been reported in individuals with phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMIDs: 22608206 (2012) and 21618646 (2011)). Based on the available information, this variant is classified as pathogenic.
Sema4, Sema4	RCV000132169	SCV002530215	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-01	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288610	SCV002580458	pathogenic	Lynch syndrome 4	2021-10-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483226	SCV002783449	pathogenic	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155080	SCV003844259	pathogenic	Hereditary nonpolyposis colon cancer	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1687C>T (p.Arg563X) 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 251330 control chromosomes (gnomAD). c.1687C>T has been reported in the literature in multiple individuals affected with colorectal cancer, and phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (example: Vaughn_2010, Vasovcak_2012, Goodenberger_2015, and Wang_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV002288610	SCV004187698	pathogenic	Lynch syndrome 4	2023-09-20	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	RCV002288610	SCV004207878	pathogenic	Lynch syndrome 4	2022-11-08	criteria provided, single submitter	clinical testing
ITMI	RCV000121846	SCV000086046	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356008	SCV001551055	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Arg563X variant was identified in 5 of 818 proband chromosomes (frequency: 0.006) from individuals or families with Lynch Syndrome, colorectal cancer, endometrial cancer, and biallelic mismatch repair deficiency (Goodenberger 2016, Haraldsdottir 2014, Jansen 2016, Vaughn 2010, Vasovcak 2012). The variant was also identified in the following databases: dbSNP (ID: rs587778618) as "With Pathogenic, Uncertain significance allele", ClinVar (3x, pathogenic), Clinvitae (2x, pathogenic), and Cosmic (3x, confirmed somatic, in carcinomas of the skin and lung). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in one individual with a family history of Lynch Syndrome. The variant was identified in control databases in 2 of 246126 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 15246 chromosomes (freq: 0.0001). The variant was not observed in the other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.