12-132687315-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePS1_ModeratePP5
The NM_006231.4(POLE):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000056 in 1,499,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006231.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151754Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000921 AC: 1AN: 108632Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 60230
GnomAD4 exome AF: 0.0000616 AC: 83AN: 1348212Hom.: 0 Cov.: 32 AF XY: 0.0000661 AC XY: 44AN XY: 665276
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151754Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74132
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2025 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2023 | 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 - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 02, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 11, 2021 | - - |
Colorectal cancer, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 30, 2017 | - - |
POLE-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2024 | 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. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 12, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at