Submissions for variant NM_000535.7(PMS2):c.1874del (p.Ser624_Leu625insTer) (rs786203073)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166215	SCV000216994	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-25	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae	RCV000229520	SCV000285091	pathogenic	Hereditary nonpolyposis colon cancer	2019-10-29	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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 26895986, 25856668). ClinVar contains an entry for this variant (Variation ID: 186596). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413904	SCV000490732	pathogenic	not provided	2018-07-13	criteria provided, single submitter	clinical testing	This deletion of one nucleotide is denoted PMS2 c.1874delT at the cDNA level and p.Leu625Ter (L625X) at the protein level. The normal sequence, with the base that is deleted in brackets, is TCTT[delT]AGCT. The deletion creates a nonsense variant, which changes a Leucine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with colon cancer (Goodenberger 2015, Rosty 2016, Pearlman 2017). At least one tumor showed absence of PMS2 via mismatch repair immunohistochemistry and/or mismatch repair deficiency (Pearlman 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413904	SCV000601831	pathogenic	not provided	2016-06-24	criteria provided, single submitter	clinical testing
Color	RCV000166215	SCV000691048	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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.
Integrated Genetics/Laboratory Corporation of America	RCV000603093	SCV000920042	pathogenic	Lynch syndrome	2018-03-06	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 (e.g., p.Gln643X; p.Lys706fsX19). The variant allele was found at a frequency of 4.1e-06 in 246252 control chromosomes. 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.