Submissions for variant NM_000535.7(PMS2):c.1119_1122del (p.Gln374fs)

dbSNP: rs757679199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795960	SCV000935442	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-28	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: 642485). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is present in population databases (rs757679199, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln374Serfs*10) 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).
GeneDx	RCV002534590	SCV003194907	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing	Observed in an individual with PMS2-related cancers (Lerner-Ellis 2021); 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; This variant is associated with the following publications: (PMID: 32885271)
Myriad Genetics, Inc.	RCV003453647	SCV004188622	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017743	SCV004848381	likely pathogenic	Lynch syndrome	2020-05-13	criteria provided, single submitter	clinical testing	The p.Gln374SerfsX10 variant in PMS2 has not been previously reported in individuals with Lynch syndrome, but was identified in 0.002% (2/113726) of European chromosomes by gnomAD (https://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 642485). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 374 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2.
Ambry Genetics	RCV004027545	SCV005035990	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The c.1119_1122delTCAG pathogenic mutation, located in coding exon 10 of the PMS2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1119 to 1122, causing a translational frameshift with a predicted alternate stop codon (p.Q374Sfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555875	SCV005045102	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-04-09	criteria provided, single submitter	clinical testing	The PMS2 c.1119_1122del (p.Gln374Serfs*10) variant has been reported in at least one individual with a clinical diagnosis of Lynch syndrome and an immunohistochemistry consistent with loss of PMS2 (Lerner-Ellis J et al., PMID: 32885271). This variant has been reported in the ClinVar database as a germline pathogenic variant by four submitters. This variant is only observed on 2/1460,618 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting four nucleotides, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356129	SCV001551202	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Gln374Serfs*10 variant was not identified in the literature nor was it identified in ClinVar, GeneInsight-COGR, Cosmic, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs757679199). The variant was also not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.1119_1122del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 374 and leads to a premature stop codon at position 383. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. Further, this variant was identified by our laboratory in a patient with a PMS2-deficient tumour. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.