Submissions for variant NM_006231.4(POLE):c.1A>G (p.Met1Val)

dbSNP: rs878854847

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578573	SCV000543917	pathogenic	not provided	2025-01-02	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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 405608). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000573016	SCV000674330	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-02	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the POLE gene, results from an A to G 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. Another variant at this codon (c.1A>T) 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 available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000578573	SCV000680979	likely pathogenic	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Counsyl	RCV000462229	SCV000785513	uncertain significance	Colorectal cancer, susceptibility to, 12	2017-08-30	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000578573	SCV002009601	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000573016	SCV002536769	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002506102	SCV002815685	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2022-01-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355736	SCV001550699	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLE p.Met1Val variant was not identified in the literature. The variant was identified in dbSNP (rs878854847) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and Counsyl). The variant was identified in control databases in 1 of 104,900 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 1 of 8614 chromosomes (freq: 0.0001), but was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian and South Asian populations. The c.1A>G variant occurs in the first base of the translation initiation site (the methionine amino acid start site), increasing the likelihood this variant may disrupt translation and lead to an abnormal protein product. The next in-frame methionine is located at codon 44, and it is not known whether the protein is translated from an alternate start site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004533152	SCV004722102	uncertain significance	POLE-related disorder	2024-01-04	no assertion criteria provided	clinical testing	The POLE c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant disrupts the initiating methionine of POLE. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/405608/). Of note, another variant disrupting the initiating methionine of POLE (c.1A>T) has been reported in the compound heterozygous state in patients with IMAGE-1 syndrome (Nakano et al. 2022. PubMed ID: 35534205). The next downstream methionine is found at amino acid 44. To date, there have been no functional studies to determine if p.Met44 is utilized as an alternative initiation site and how it would impact protein structure or function. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.