Submissions for variant NM_000535.7(PMS2):c.2186_2187del (p.Leu729fs)

dbSNP: rs587779335

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000365642	SCV000108334	uncertain significance	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	This variant is likely to come from pseudogene
Pathway Genomics	RCV000172821	SCV000223787	likely pathogenic	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778109	SCV000469717	likely pathogenic	Lynch syndrome 4	2018-08-22	criteria provided, single submitter	clinical testing	The PMS2 c.2186_2187delTC (p.Leu729GlnfsTer6) variant results in a frameshift and is predicted to result in the premature termination of the protein. The p.Leu729GlnfsTer6 variant has been reported in three studies in which it has been identified in five individuals from three families, including in a homozygous state in one individual with familial prostate cancer and in a compound heterozygous state in four individuals with constitutional mismatch repair deficiency (De Vos et al. 2004; Bakry et al. 2014; Leongamornlert et al. 2014). Control data are unavailable for this variant which is reported at a frequency of 0.02565 in the African population of the Genome Aggregation Database but due to possible pseudogene interference the frequency data is not reliable. Based on the clinical evidence and the potential impact of frameshift variants, the p.Leu729GlnfsTer6 variant is classified as likely pathogenic for Lynch syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000544078	SCV000625597	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-08-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu729Glnfs*6) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected prostate cancer and constitutional mismatch repair deficiency syndrome (PMID: 24556621, 15077197). This variant is also known as c.2184delTC in the literature. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000573464	SCV000663442	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	The c.2186_2187delTC pathogenic mutation, located in coding exon 13 of the PMS2 gene, results from a deletion of two nucleotides at nucleotide positions 2186 to 2187, causing a translational frameshift with a predicted alternate stop codon (p.L729Qfs*6). Two individuals whose clinical histories were consistent with CMMRD were found to be compound heterozygotes for this and another PMS2 mutation (Bakry D et al. Eur. J. Cancer 2014 Mar; 50(5):987-96). This pathogenic mutation has also been detected in the PMS2 pseudogene region in multiple individuals (De Vos M et al. Am. J. Hum. Genet. 2004 May;74(5):954-64; Leongamornlert D et al. Br. J. Cancer 2014 Mar;110(6):1663-72). This alteration has been classified as an uncertain variant using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies. The uncertain variant classification by the insight group is noted to be due to the possibility that this variant is located in the PMS2CL pseudogene (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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 when not in the pseudogene.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293420	SCV000697339	pathogenic	Hereditary nonpolyposis colon cancer	2022-02-10	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2186_2187delTC (p.Leu729GlnfsX6, also reported in the literature with legacy name c.2184delTC) 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 0.0019 in 235662 control chromosomes in the gnomAD database, including 4 homozygotes, however this frequency data may not be reliable for this region of PMS2 known to have significant sequence overlap with pseudogenes, and it is not known whether pseudogene amplification was ruled out in these samples. This variant has been frequently identified as a non-reportable variant originating in the PMS2 pseudogene in specimens with bonafide pathogenic variation in other genes among patients undergoing multigene panel testing at our laboratory. Therefore, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2186_2187delTC has been reported in the literature in compound heterozygosity with another PMS2 variant in a family with two siblings affected with Turcot Syndrome (c.400C>T, p.R134*, e.g. DeVos_2004; patients originally described by Hamilton et al, 1995 and subsequently cited in multiple publications) and Constitutional Mismatch Repair Deficiencies (CMMRD) (c.134A>C, p.Asn45Thr, e.g. Bakry_2014). The authors report pseudogene amplification as having been ruled out in these studies. These data indicate that the variant was likely to be associated with disease in these individuals. The variant has also been reported in individuals with other cancer types, including breast (e.g. Eliade_2017, Gardner_2018) and prostate (Leongamornlert_2014), although no co-segregation evidence was reported, and in at least some of these cases, it is not clear whether pseudogene interference was ruled out. At least two publications report experimental evidence that a lymphoblastoid cell line and/or tumor tissue from a compound heterozygous patient with bi-allelic PMS2 mutations, including this one, had nearly null expression of PMS2 by IHC, however the contributions of the individual variants to these findings cannot be determined based upon this data alone (e.g. Turnbull_2012, Bakry_2014). Multiple clinical diagnostic laboratories and one expert panel (InSight) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Uncertain significance, n=4 to include the expert panel; Pathogenic/Likely Pathogenic, n=3). Some submitters cite overlapping evidence cited in the context of our evaluation. Based on the evidence outlined above, this variant was classified as pathogenic within settings of unequivocal confirmation of its origin within the PMS2 gene.
Mendelics	RCV000365642	SCV000838170	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000778109	SCV001137281	uncertain significance	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009819	SCV001428529	uncertain significance	Mismatch repair cancer syndrome 1	2018-08-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267843	SCV002550691	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415835	SCV004106507	likely pathogenic	PMS2-related condition	2024-02-13	criteria provided, single submitter	clinical testing	The PMS2 c.2186_2187delTC variant is predicted to result in a frameshift and premature protein termination (p.Leu729Glnfs*6). This variant (also known as 2184delTC) has been reported in 13 patients with a personal or family history of breast or ovarian cancer (Supplemental File 1, Lerner-Ellis et al. 2020. PubMed ID: 32885271). This variant has been reported in the compound heterozygous state in two siblings with Turcot syndrome (De Vos et al. 2004. PubMed ID: 15077197) and an individual with constitutional mismatch repair deficiency (Patient MMR50, Bakry et al. 2014. PubMed ID: 24440087). It has also been reported in the homozygous state in an individual with a personal and family history of prostate cancer (Patient Prs14, Leongamornlert et al. 2014. PubMed ID: 24556621). This variant is reported in 2.5% of alleles in individuals of African descent in gnomAD. This variant falls within a highly paralogous region and allele frequency data should be interpreted with caution. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/91330). Frameshift variants in PMS2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003436927	SCV004163706	benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	PMS2: BS1, BS2
Myriad Genetics, Inc.	RCV000778109	SCV004188576	pathogenic	Lynch syndrome 4	2023-09-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492428	SCV004239593	uncertain significance	Breast and/or ovarian cancer	2023-06-09	criteria provided, single submitter	clinical testing
OMIM	RCV001267877	SCV000030040	pathogenic	Mismatch repair cancer syndrome 4	2004-05-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353688	SCV000592946	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p.Leu729GlnfsX6 variant was identified in 1 of 382 proband chromosomes (frequency: 0.003) from British individuals or families with prostate cancer (Leongamornlert 2014). The variant was also identified in children affected with CMMRD (constitutional mismatch repair deficiency syndrome), co-occurring with a pathogenic PMS2 variant (R134X) in 3 studies (Bonthron 2005, Bakry 2014, De Vos 2004). The variant was identified in dbSNP (ID: rs587779335) “With Pathogenic allele”, ClinVar (uncertain significance, reviewed by an expert panel (2015); submitters: uncertain significance by InSIGHT, likely pathogenic by Pathway Genomics, likely benign by Illumina Clinical Services and pathogenic by OMIM), Clinvitae (3X), Insight Colon Cancer Gene Variant Database (Class 5), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (1x class 5), and was not identified in GeneInsight – COGR (unavailable), Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 419 (4 homozygous) of 231598 chromosomes at a frequency of 0.009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 349 (4 homozygous) of 13606 chromosomes (frequency: 0.03), Other in 8 of 5246 chromosomes (frequency: 0.002), Latino in 42 of 32934 chromosomes (frequency: 0.001), European Non-Finnish in 16 of 102684 chromosomes (frequency: 0.0002), Ashkenazi Jewish in 3 of 9570 chromosomes (frequency: 0.0003), South Asian in 1 of 29508 chromosomes (frequency: 0.00003). The c.2186_2187del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 729 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PMS2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.