Submissions for variant NM_000535.7(PMS2):c.1376C>G (p.Ser459Ter)

dbSNP: rs587780724

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000439409	SCV000536465	pathogenic	not provided	2019-11-29	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; Observed in the homozygous state in one individual with a hematologic malignancy in childhood (Oberg 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28007021, 25883011, 31130284, 32359129)
Invitae	RCV000629760	SCV000750716	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-06-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant has been reported as homozygous in an individual affected with T-cell lymphoblastic lymphoma (PMID: 28007021). ClinVar contains an entry for this variant (Variation ID: 393103). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser459*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV001011228	SCV001171526	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-07	criteria provided, single submitter	clinical testing	The p.S459* pathogenic mutation (also known as c.1376C>G), located in coding exon 11 of the PMS2 gene, results from a C to G substitution at nucleotide position 1376. This changes the amino acid from a serine to a stop codon within coding exon 11. The p.S459* alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This alteration was also reported as homozygous in a pediatric patient with acute lymphoblastic leukemia (ALL) and constitutional mismatch repair deficiency (CMMRD) was implicated (Oberg JA et al. Genome Med, 2016 12;8:133). In addition to the clinical data presented in the literature, 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.
Color Diagnostics, LLC DBA Color Health	RCV001011228	SCV001344542	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the PMS2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.
Myriad Genetics, Inc.	RCV003449099	SCV004187789	pathogenic	Lynch syndrome 4	2023-09-20	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003449099	SCV004611133	pathogenic	Lynch syndrome 4	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser459*) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with T-cell lymphoblastic lymphoma (PMID: 28007021). ClinVar contains an entry for this variant (Variation ID: 393103). For these reasons, this variant has been classified as Pathogenic. Heterozygous pathogenic/likely pathogenic variants in the PMS2 cause hereditary non-polyposis colorectal cancer syndrome, also known as Lynch Syndrome.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985175	SCV001133184	likely pathogenic	Mismatch repair cancer syndrome 1	2019-09-26	no assertion criteria provided	clinical testing