Submissions for variant NM_000535.7(PMS2):c.1571dup (p.Gly525fs)

dbSNP: rs1554297534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573779	SCV000663468	pathogenic	Hereditary cancer-predisposing syndrome	2016-01-12	criteria provided, single submitter	clinical testing	The c.1571dupC pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a duplication of C at nucleotide position 1571, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in the homozygous state in a 13y/o male with Constitutional MisMatch Repair Deficiency (CMMRD) syndrome (Urganci N et al. Pediatrics. 2015 Oct;136(4):e1047-50). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV001390619	SCV001592409	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 480313). This premature translational stop signal has been observed in individual(s) with constitutional mismatch repair deficiency (PMID: 26391938). This sequence change creates a premature translational stop signal (p.Gly525Argfs*17) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222552	SCV002500379	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-03-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1571dupC (p.Gly525ArgfsX17) 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 251080 control chromosomes. To our knowledge, no occurrence of c.1571dupC in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Bothlaboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003451226	SCV004187709	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	RCV003451226	SCV004207911	pathogenic	Lynch syndrome 4	2022-01-27	criteria provided, single submitter	clinical testing