Submissions for variant NM_000535.7(PMS2):c.2155C>T (p.Gln719Ter)

gnomAD frequency: 0.00001  dbSNP: rs876659480

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219006	SCV000276004	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-13	criteria provided, single submitter	clinical testing	The p.Q719* pathogenic mutation (also known as c.2155C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2155. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation was reported in one family from a cohort of 98 PMS2 positive families (ten Broeke SW et al. J. Clin. Oncol. 2015 Feb; 33(4):319-25). This mutation was also reported in two Dutch probands diagnosed at ages 44 and 57 with MSI-H colorectal cancer and both tumors demonstrated loss of PMS2 expression by immunohistochemistry (van der Klift HM et al. Hum Mutat, 2016 11;37:1162-1179). In a cohort of European PMS2 mutation carriers, this variant was identified in three carriers (3/381) from two different families (2/130) (Suerink M et al. Genet Med, 2016 Apr;18:405-9). This mutation was also reported as homozygous in a 19 year old male proband diagnosed with colorectal cancer and leukemia in addition to having a family history of cancer (Arslan Ates E et al. Medeni Med J, 2022 Jun;37:150-158). 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	RCV000482925	SCV000569464	pathogenic	not provided	2018-04-03	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted PMS2 c.2155C>T at the cDNA level and p.Gln719Ter (Q719X) 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 identified in families with Lynch syndrome and in one individual with colorectal cancer displaying microsatellite instability and absence of PMS2 protein via immunohistochemistry (IHC) (Guerts-Giele 2014, Suerink 2015, ten Broeke 2015). We consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000482925	SCV000884399	pathogenic	not provided	2017-06-23	criteria provided, single submitter	clinical testing	The PMS2 c.2155C>T;p.Gln719Ter variant has been described in at least one family with a clinical diagnosis of Lynch syndrome (ten Broeke 2015). The variant is listed in the ClinVar database (Variation ID: 231993), but is not listed in the dbSNP variant database. The variant is listed in the Genome Aggregation Database with an allele frequency of 0.0008622 percent (2/231974 alleles). This variant introduces a premature termination codon and is predicted to result in a truncated or absent protein. Considering available information, this variant is classified as pathogenic. References: ten Broeke SW et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015 Feb 1;33(4):319-25.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193969	SCV001363166	pathogenic	Hereditary nonpolyposis colon cancer	2019-01-16	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2155C>T (p.Gln719X) 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 (NMD), which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.6e-06 in 231974 control chromosomes (gnomAD). c.2155C>T has been reported in the literature in individuals affected with Lynch Syndrome (Suerink 2015, ten Broeke 2015, van der Klift 2016), where in two patients the associated tumors lacked the PMS2 protein and displayed microsatellite instability (van der Klift 2016). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence, demonstrating the lack of mRNA, probably due to NMD (Suerink 2015, van der Klift 2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV002515651	SCV003439526	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 231993). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome and/or prostate cancer (PMID: 25512458, 31948886). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change creates a premature translational stop signal (p.Gln719*) 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).
Myriad Genetics, Inc.	RCV003454638	SCV004188624	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.