Submissions for variant NM_000535.7(PMS2):c.1275_1279del (p.Leu426fs)

dbSNP: rs1554297962

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615628	SCV000713113	pathogenic	Lynch syndrome	2017-06-12	criteria provided, single submitter	clinical testing	The p.Leu426fs variant in PMS2 has not been previously reported in individuals w ith Lynch syndrome or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 426 and leads to a premature termination codon 30 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of function of the PMS2 gene is an established dise ase mechanism in Lynch syndrome. In summary, this variant meets criteria to be c lassified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein and absence in controls.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759194	SCV000888387	pathogenic	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Invitae	RCV001860254	SCV002234253	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-30	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: 505722). 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.Leu426Serfs*30) 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).
Ambry Genetics	RCV002377243	SCV002687617	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	clinical testing	The c.1275_1279delTCTTC pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1275 to 1279, causing a translational frameshift with a predicted alternate stop codon (p.L426Sfs*30). 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.
Myriad Genetics, Inc.	RCV003451374	SCV004188658	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.
All of Us Research Program, National Institutes of Health	RCV000615628	SCV004825219	pathogenic	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides 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 PMS2-related disorders 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.