Submissions for variant NM_000535.7(PMS2):c.1297A>T (p.Lys433Ter)

dbSNP: rs863224496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneKor MSA	RCV000708622	SCV000821767	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a single amino acid change from Lysine to a premature translational stop signal at codon 433 of the PMS2 protein. This is expected to result in a truncated, non-functional protein product. Truncating variants in the PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747).The mutation database ClinVar contains entries for this variant (Variation ID:216073).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268094	SCV001446746	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001268094	SCV001469605	pathogenic	not provided	2020-04-09	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Invitae	RCV001389426	SCV001590788	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-07-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys433*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 216073). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000708622	SCV002692406	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	The p.K433* pathogenic mutation (also known as c.1297A>T), located in coding exon 11 of the PMS2 gene, results from an A to T substitution at nucleotide position 1297. This changes the amino acid from a lysine to a stop codon within coding exon 11. This alteration has been reported as pathogenic in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
Myriad Genetics, Inc.	RCV003454500	SCV004188673	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.