Submissions for variant NM_000535.7(PMS2):c.139_146del (p.Leu47fs)

dbSNP: rs886039615

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254823	SCV000322529	likely pathogenic	not provided	2015-12-30	criteria provided, single submitter	clinical testing	This deletion of 8 nucleotides in PMS2 is denoted c.139_146delCTGGATGC at the cDNA level and p.Leu47TrpfsX4 (L47WfsX4) at the protein level. The normal sequence, with the bases that are deleted in braces, is CAGT[CTGGATGC]TGGT. The deletion causes a frameshift, which changes a Leucine to a Tryptophan at codon 47, 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. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Ambry Genetics	RCV000575861	SCV000663554	pathogenic	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing	The c.139_146delCTGGATGC pathogenic mutation, located in coding exon 2 of the PMS2 gene, results from a deletion of 8 nucleotides at nucleotide positions 139 to 146, causing a translational frameshift with a predicted alternate stop codon (p.L47Wfs*4). 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.	RCV003454781	SCV004188694	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090300	SCV005745628	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu47Trpfs*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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 265547). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.