Submissions for variant NM_000535.7(PMS2):c.1874del (p.Ser624_Leu625insTer)

dbSNP: rs786203073

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166215	SCV000216994	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-27	criteria provided, single submitter	clinical testing	The c.1874delT pathogenic mutation, located in coding exon 11 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 1874, causing a translational frameshift with a predicted alternate stop codon (p.L625*). This mutation has been detected in multiple individuals with Lynch syndrome-associated cancers and several with tumors showing loss of PMS2 staining on IHC (Goodenberger ML et al. Genet Med, 2016 Jan;18:13-9; Rosty C et al. BMJ Open, 2016 Feb;6:e010293; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Ranola JMO et al. Fam Cancer, 2019 01;18:67-73; Ambry internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229520	SCV000285091	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu625*) 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 present in population databases (rs786203073, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 25856668, 26895986). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PMS2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for PMS2 testing. ClinVar contains an entry for this variant (Variation ID: 186596). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413904	SCV000490732	pathogenic	not provided	2024-10-02	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26895986, 25856668, 27978560, 28514183, 30787465, 31447099, 32719484, 29345684, 30019097)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413904	SCV000601831	pathogenic	not provided	2021-01-27	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of PMS2 protein synthesis. It has been reported in individuals affected with colorectal cancer in the published literature (PMID: 26895986 (2016), 27978560 (2016)). Therefore, the variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166215	SCV000691048	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 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, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 25856668, 26895986, 27978560). Tumor data from affected individuals has demonstrated deficient mismatch repair and loss of PMS2 protein via immunohistochemistry (PMID: 25856668, 27978560). This variant has been identified in 1/251448 chromosomes 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603093	SCV000713114	pathogenic	Lynch syndrome	2017-06-12	criteria provided, single submitter	clinical testing	The p.Leu625X variant in PMS2 has been reported in at least 1 individual with a Lynch syndrome-associated cancer (Rosty 2016, Goodenberger 2016) and has also be en reported in ClinVar (Variation ID 186596). It was also identified in 1/111710 of European chromosomes by the Genome Aggregation Database (gnomAD; http://gnom ad.broadinstitute.org). This nonsense variant is a result of a deletion of 1 bas e at position 1874, which creates a premature termination codon at amino acid po sition 625. This alteration is then predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of function of the PMS2 gene is an establ ished disease mechanism in Lynch syndrome. In summary, this variant meets criter ia to be classified as pathogenic for Lynch syndrome in an autosomal dominant ma nner based upon its absence from controls and predicted impact to the protein an d low frequency in controls.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000413904	SCV000885995	pathogenic	not provided	2018-02-13	criteria provided, single submitter	clinical testing	The PMS2 c.1874delT; p.Leu625Ter variant (rs786203073) has been reported in individuals with colorectal cancer (Goodenberger 2016, Rosty 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 186596) and is seen in the general population at a low overall frequency of 0.0004% (1/246252 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Goodenberger M et al. PMS2 monoallelic mutation carriers: the known unknown. Genet Med. 2016 Jan; 18(1): 13–19. Rosty C et al. Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort. BMJ Open. 2016 Feb 19;6(2):e010293.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797652	SCV000920042	pathogenic	Hereditary nonpolyposis colon cancer	2021-11-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1874delT (p.Leu625X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251448 control chromosomes (gnomAD). The c.1874delT variant has been reported in the literature in multiple individuals affected with Lynch Syndrome, though one 66 year old individual carrying the variant was unaffected (Goodenberger_2016), suggesting the possibility of reduced penetrance or later onset. However, these data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003454412	SCV004187686	pathogenic	Lynch syndrome 4	2023-09-21	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.
Baylor Genetics	RCV003454412	SCV004207872	pathogenic	Lynch syndrome 4	2023-12-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000413904	SCV004226928	pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	PP4, PM2, PVS1
All of Us Research Program, National Institutes of Health	RCV000603093	SCV005429557	pathogenic	Lynch syndrome	2024-08-03	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 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, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated disease (PMID: 25856668, 26895986, 27978560). Tumor data from affected individuals has demonstrated deficient mismatch repair and loss of PMS2 protein via immunohistochemistry (PMID: 25856668, 27978560). This variant has been identified in 1/251448 chromosomes 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.
PreventionGenetics, part of Exact Sciences	RCV004742295	SCV005349255	pathogenic	PMS2-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The PMS2 c.1874delT variant is predicted to result in premature protein termination (p.Leu625*). This variant has been reported in individuals with colorectal cancer (Table S1, Goodenberger et al. 2016. PubMed ID: 25856668; Supplementary Table 2, Rosty et al. 2016. PubMed ID: 26895986; eTable 3, Pearlman et al. 2017. PubMed ID: 27978560). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186596/?new_evidence=true). Nonsense variants in PMS2 are expected to be pathogenic. This variant is interpreted as pathogenic.