Submissions for variant NM_000535.7(PMS2):c.709C>T (p.Gln237Ter)

gnomAD frequency: 0.00001  dbSNP: rs1458321358

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507540	SCV000601857	likely pathogenic	not provided	2017-05-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530268	SCV000625682	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln237*) 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: 439245). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000662813	SCV000785649	likely pathogenic	Lynch syndrome 4	2017-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026032	SCV001188335	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.Q237* pathogenic mutation (also known as c.709C>T), located in coding exon 7 of the PMS2 gene, results from a C to T substitution at nucleotide position 709. This changes the amino acid from a glutamine to a stop codon within coding exon 7. 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.	RCV000662813	SCV004019728	pathogenic	Lynch syndrome 4	2023-04-03	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.
All of Us Research Program, National Institutes of Health	RCV004003553	SCV004839929	pathogenic	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported by several laboratories in the ClinVar database (Variation ID: 439245). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
GeneDx	RCV000507540	SCV005078672	pathogenic	not provided	2023-12-09	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
deCODE genetics, Amgen	RCV000662813	SCV004022258	likely pathogenic	Lynch syndrome 4	2023-07-21	no assertion criteria provided	research	The variant NM_000535.7:c.709C>T (chr7:5997420) in PMS2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.