Submissions for variant NM_000535.7(PMS2):c.756_757del (p.Cys252_Glu253delinsTer)

dbSNP: rs1064794905

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481690	SCV000570185	pathogenic	not provided	2023-09-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481690	SCV000889639	likely pathogenic	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026570	SCV001188976	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-17	criteria provided, single submitter	clinical testing	The c.756_757delTG variant, located in coding exon 7 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 756 to 757, causing a translational frameshift with a predicted alternate stop codon (p.C252*). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851199	SCV002121270	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-07-08	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: 421093). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys252*) 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).
Baylor Genetics	RCV003147481	SCV003836183	likely pathogenic	Lynch syndrome 4	2022-02-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003147481	SCV004188656	pathogenic	Lynch syndrome 4	2023-09-19	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV001026570	SCV004359660	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 7 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 hereditary cancer 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.