Submissions for variant NM_000535.7(PMS2):c.802del (p.Tyr268fs)

dbSNP: rs267608149

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183135	SCV001348792	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the PMS2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. 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.
Ambry Genetics	RCV001183135	SCV002675976	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The c.802delT variant, located in coding exon 7 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 802, causing a translational frameshift with a predicted alternate stop codon (p.Y268Tfs*39). 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.
Invitae	RCV002559044	SCV003289934	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-01-06	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: 922836). 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.Tyr268Thrfs*39) 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	RCV003396795	SCV004122899	pathogenic	Hereditary nonpolyposis colon cancer	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.802delT (p.Tyr268ThrfsX39) 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. The variant was absent in 248408 control chromosomes (gnomAD). To our knowledge, no occurrence of c.802delT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014, and all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003449600	SCV004187795	pathogenic	Lynch syndrome 4	2023-09-19	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	RCV004017793	SCV004847768	likely pathogenic	Lynch syndrome	2019-05-08	criteria provided, single submitter	clinical testing	The p.Tyr268ThrfsX39 variant in PMS2 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 268 and leads to a premature termination codon 39 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Another frameshift PMS2 variant altering the protein's sequence at the same position (p.Tyr268LeufsX31) has been classified as Pathogenic by our laboratory and by the ClinGen-approved InSIGHT expert panel. 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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249993	SCV001424007	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing