Submissions for variant NM_000535.7(PMS2):c.851del (p.Ser283_Ser284insTer)

dbSNP: rs876658964

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215549	SCV000274855	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-25	criteria provided, single submitter	clinical testing	The c.851delC pathogenic mutation, located in coding exon 8 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 851, causing a translational frameshift with a predicted alternate stop codon (p.S284*). This mutation has been identified in a patient undergoing multi-gene panel testing for a personal and/or family history of cancer (Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575). 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	RCV000479888	SCV000569360	pathogenic	not provided	2022-04-15	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual undergoing multigene panel testing in the published literature (Espenschied 2017); This variant is associated with the following publications: (PMID: 28514183)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589130	SCV000697391	likely pathogenic	Lynch syndrome	2017-07-10	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.851delC (p.Ser284X) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 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 (e.g. c.861_864delACAG, p.Arg287fsX19; c.1021delA, p.Arg341fsX15; c.1164delT, p.His388fsX10). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121008 control chromosomes and has been reported in the literature in a cohort of individuals being tested by a multi-gene panel, with no phenotype data provided for the individual carrying the variant (Espenschied_2017). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003454630	SCV004187674	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	RCV003454630	SCV004207895	pathogenic	Lynch syndrome 4	2022-06-24	criteria provided, single submitter	clinical testing
Invitae	RCV003758730	SCV004449580	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-27	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: 231108). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser284*) 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).