Submissions for variant NM_006231.4(POLE):c.4872G>A (p.Trp1624Ter)

gnomAD frequency: 0.00002  dbSNP: rs754982151

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657745	SCV000544099	pathogenic	not provided	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1624*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is present in population databases (rs754982151, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405778). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000575334	SCV000671317	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-18	criteria provided, single submitter	clinical testing	The p.W1624* variant (also known as c.4872G>A), located in coding exon 37 of the POLE gene, results from a G to A substitution at nucleotide position 4872. This changes the amino acid from a tryptophan to a stop codon within coding exon 37. This alteration has been identified in a cohort of individuals with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res. 2020 Jun;30(3):247-251). This amino acid position is highly conserved in available vertebrate species. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000657745	SCV000779497	likely pathogenic	not provided	2023-09-13	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); Observed in individuals with melanoma or renal cell carcinoma (Lu et al., 2015; Li et al., 2020; Demidova et al., 2023); This variant is associated with the following publications: (PMID: 28873162, 26689913, 31567591, 37095444)
Counsyl	RCV000472467	SCV000786583	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-05-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657745	SCV002048478	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing	The POLE c.4872G>A; p.Trp1624Ter variant (rs754982151), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 405778). This variant is found on a single chromosome (1/31386 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. However, the established disease mechanism in POLE involves missense variants in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Given the lack of clinical and functional data, the significance of the p.Trp1624Ter variant is uncertain at this time. References: Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000472467	SCV002525974	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-01-14	criteria provided, single submitter	clinical testing	The POLE c.4872G>A (p.Trp1624Ter) change is a nonsense variant that is predicted to cause premature protein truncation. The disease mechanism for replication-repair-associated DNA polymerases is loss of proofreading caused by missense changes in the exonuclease domain, whereas protein-truncating variants causing loss-of-function do not have an established correlation to disease (PMID: 23447401). This variant is located at the c-terminal end of the gene and does not affect the exonuclease domain. This variant has a maximum subpopulation frequency of 0.0064% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/12-133219172-C-T). This variant has been reported in one hypermutated tumor, as well as in three tumors with low mutational burden (PMID: 29056344). It has also been reported in an individual with renal clear cell carcinoma (PMID: 29625052). To our knowledge, this variant has not been reported in individuals with POLE-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting.