Submissions for variant NM_000535.7(PMS2):c.116del (p.Val39fs)

dbSNP: rs1064794152

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483540	SCV000567993	pathogenic	not provided	2015-09-21	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in PMS2 is denoted c.116delT at the cDNA level and p.Val39GlufsX4 (V39EfsX4) at the protein level. The normal sequence, with the base that is deleted in braces, is GCGG[T]AAAG. The deletion causes a frameshift, which changes a Valine to a Glutamic Acid at codon 39, and creates a premature stop codon at position 4 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483540	SCV001469600	likely pathogenic	not provided	2019-12-31	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality.
Invitae	RCV001851174	SCV002143719	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-23	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: 419857). 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.Val39Glufs*4) 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	RCV002329147	SCV002631689	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	clinical testing	The c.116delT pathogenic mutation, located in coding exon 2 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 116, causing a translational frameshift with a predicted alternate stop codon (p.V39Efs*4). This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of PMS2 expression by immunohistochemistry (Ambry internal data). 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.	RCV003449200	SCV004187791	pathogenic	Lynch syndrome 4	2023-09-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.