Submissions for variant NM_000535.7(PMS2):c.2397_2400dup (p.Ser801fs)

dbSNP: rs2128672594

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001884593	SCV002158009	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PMS2 protein in which other variant(s) (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 26116798, 30764633; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with prostate cancer (PMID: 31948886). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This sequence change creates a premature translational stop signal (p.Ser801Alafs*24) in the PMS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 62 amino acid(s) of the PMS2 protein.
Ambry Genetics	RCV002449543	SCV002732428	pathogenic	Hereditary cancer-predisposing syndrome	2024-12-04	criteria provided, single submitter	clinical testing	The c.2397_2400dupGCCT pathogenic mutation, located in coding exon 14 of the PMS2 gene, results from a duplication of GCCT at nucleotide position 2397, causing a translational frameshift with a predicted alternate stop codon (p.S801Afs*24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration occurs at the 3' terminus of the PMS2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 7% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003452079	SCV004187681	pathogenic	Lynch syndrome 4	2023-09-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003452079	SCV004203426	likely pathogenic	Lynch syndrome 4	2021-03-05	criteria provided, single submitter	clinical testing