Submissions for variant NM_006231.4(POLE):c.1A>T (p.Met1Leu)

dbSNP: rs878854847

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000679609	SCV000289279	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the POLE mRNA. The next in-frame methionine is located at codon 44. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive FILS syndrome (PMID: 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 240415). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000679609	SCV000293771	uncertain significance	not provided	2018-10-12	criteria provided, single submitter	clinical testing	The c.1A>T variant in the POLE gene alters the initiator Methionine codon, and the resultant protein would be described as ?p.Met1?? to signify that it is not known if the loss of Met1 prevents all protein translation or if an abnormal protein is produced using an alternate Methionine codon. This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. POLE c.1A>T was observed at an allele frequency of 0.01% (4/37,104) in individuals of European ancestry in large population cohorts (Lek 2016). While some missense variants have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLE c.1A>T to be a variant of unknown significance with respect to cancer. To date, the majority of publications regarding POLE and colorectal cancer risk are confined to missense variants within the exonuclease domain (Palles 2013, Spier 2015). However, a splice variant and a frameshift variant have been reported. Pachlopnik Schmid et al. (2012) observed a splice variant at the +3 position in intron 34, in the homozygous state, in 11 family members with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) from a large consanguineous family; however, they noted that all heterozygous carriers were asymptomatic and did not have a history of cancer. While Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, no family history was provided and segregation analysis was not completed. As described above, facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) appears to be a rare autosomal recessive condition associated with two loss-of-function variants in POLE (Pachlopnik Schmid 2012). For individuals and family members of reproductive age, assessment of the reproductive risk associated with being a carrier of a potential loss of function POLE variant may be considered.
Counsyl	RCV000231516	SCV000489354	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563871	SCV000671415	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-21	criteria provided, single submitter	clinical testing	The p.M1L variant (also known as c.1A>T), located in coding exon 1 of the POLE gene, results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, loss of function of POLE has not been clearly established as a mechanism of disease for colorectal cancer (CRC)/polyposis risk. This alteration has been reported in the compound heterozygous state with a pathogenic POLE mutation in individuals with intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) syndrome (Logan CV et al. Am J Hum Genet, 2018 12;103:1038-1044). However, there is an in-frame methionine 43 amino acids downstream from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on the supporting evidence, the clinical significance of this alteration for CRC/polyposis risk and IMAGe syndrome is unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235594	SCV000712555	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	The p.Met1? variant in POLE has not been previously reported in individuals with colorectal cancer (CRC). Data from large population studies is insufficient to assess its frequency (due to a lack of coverage). This variant disrupts the tran slation initiation start codon (ATG). Although this expected to severely impact the protein the precise effect is unclear. In addition, the POLE gene has not ye t been widely studied and to date, virtually all variants reported in patients w ith CRC represent missense changes. In summary, the clinical significance of the p.Met1? variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003891815	SCV000806733	uncertain significance	POLE-related condition	2024-01-10	criteria provided, single submitter	clinical testing	The POLE c.1A>T variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported with a second putative loss-of-function variant, in three individuals from two families with IMAGe syndrome (Logan et al. 2018. PubMed ID: 30503519). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133263901-T-A). To date, null variants have not been conclusively shown to cause autosomal dominant colorectal cancer susceptibility. In ClinVar, this variant has conflicting classifications including uncertain significance and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/240415/). Five additional start-loss changes in POLE are documented in gnomAD, and interpreted as variants of uncertain significance in ClinVar, and to our knowledge, none of these have been reported in the literature as causative for disease. Although we suspect this variant may be pathogenic for autosomal recessive IMAGe syndrome, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679609	SCV001134690	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000679609	SCV004226399	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing	PM2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235594	SCV004242583	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV000757962	SCV000886486	pathogenic	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2019-02-26	no assertion criteria provided	literature only