ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1687C>T (p.Arg563Ter) (rs587778618)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132169 SCV000187247 pathogenic Hereditary cancer-predisposing syndrome 2018-05-14 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. The reported patient appeared to be homozygous for this mutation, which is consistent with constitutional mismatch repair deficiency (CMMR-D) syndrome; however, non-amplification of the maternal allele was suspected since only the father tested positive for this mutation (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). 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). 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 2017-07-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1687C>T at the cDNA level and p.Arg563Ter (R563X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), 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 the compound heterozygous state, with a PMS2 multi-exonic deletion, in an individual with childhood-onset rectal cancer, caf?-au-lait spots, and immunohistochemistry demonstrating an absence of PMS2 protein in the rectal tumor as well as the normal mucosa, consistent with constitutional mismatch repair deficiency (CMMR-D) (Vaughn 2010). PMS2 Arg536Ter has also been reported in an individual with a pediatric brain tumor and NF1 phenotype, suspected for CMMR-D but the second variant was not established, and in the homozygous state in a pediatric patient with AML and osteosarcoma (Vasovcak 2012, Ortiz 2016). We consider this variant to be pathogenic.
Invitae RCV000530464 SCV000625550 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-24 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. This variant is present in population databases (rs587778618, ExAC 0.02%). This variant has been observed in individuals affected with colorectal cancer, and in one of the cases, the individual was also affected with breast cancer (PMID: 25856668). In addition, this variant has been observed as homozygous or compound heterozygous in individuals with phenotypes consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 20205264, 22608206). ClinVar contains an entry for this variant (Variation ID: 135067). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color RCV000132169 SCV000686154 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000222921 SCV000888400 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing
ITMI RCV000121846 SCV000086046 not provided not specified 2013-09-19 no assertion provided reference population

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