Submissions for variant NM_000535.7(PMS2):c.1743del (p.Glu582fs)

dbSNP: rs1057517801

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412980	SCV000490731	pathogenic	not provided	2023-08-04	criteria provided, single submitter	clinical testing	Frameshift 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; Published functional studies demonstrate decreased mismatch repair ability (Shuen et al., 2019); Observed in an individual with CMMR-D who also harbored a multi-exon duplication, variant phase information not provided (Shuen et al., 2019); This variant is associated with the following publications: (PMID: 30787465, 32719484, 30608896)
Invitae	RCV000551730	SCV000625556	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu582Lysfs*13) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 372470). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000561668	SCV000670745	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	clinical testing	The c.1743delA pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1743, causing a translational frameshift with a predicted alternate stop codon (p.E582Kfs*13). This mutation was reported in conjunction with a PMS2 EX11_12dup mutation in a patient with constitutional mismatch repair deficiency (CMMRD) syndrome. This individual had a personal history of colorectal cancer at age 23 and small bowel cancer at 30 that showed loss of PMS2 staining by IHC (Shuen AY et al. J Clin Oncol, 2019 02;37:461-470). 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.
Color Diagnostics, LLC DBA Color Health	RCV000561668	SCV002052394	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 of the PMS2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222501	SCV002500622	pathogenic	Hereditary nonpolyposis colon cancer	2022-03-24	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1743delA (p.Glu582LysfsX13) 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 was absent in 251348 control chromosomes. c.1743delA has been reported in the literature along with a PMS2 exon 11-12 duplication in at-least one individual with a confirmed case of Constitutional Mismatch Repair Deficiency (CMMRD) and in at-least one out of 26,906 participants undergoing carrier screening for autosomal dominant conditions in the Healthy Nevada Project (example, Shuen_2019, Grzymski_2020). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003449033	SCV004187694	pathogenic	Lynch syndrome 4	2023-09-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003449033	SCV004205448	pathogenic	Lynch syndrome 4	2023-09-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000412980	SCV004218964	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the PMS2 mRNA and causes the premature termination of PMS2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome-associated disease (PMID: 32719484 (2020), 30608896 (2019)) and has been reported to damage protein function (PMID: 30608896 (2019)). Based on the available information, this variant is classified as pathogenic.