ClinVar Miner

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

gnomAD frequency: 0.00019  dbSNP: rs878854847
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759267 SCV000543891 pathogenic not provided 2023-11-22 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: 405585). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000575992 SCV000671649 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the POLE gene, results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. However, there exists a possible alternate initiation site just 43 residues downstream. This amino acid position is well conserved on limited sequence alignment. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation. However, as neither this specific alteration nor loss-of-function as a mechanism of pathogenicity have been well-described in the POLE gene, the clinical significance of this variant remains unknown.
GeneDx RCV000759267 SCV000680963 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing This variant 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 isproduced using an alternate Methionine codon. POLE c.1A>C has not been previously published as a pathogenicvariant, nor has it been reported as a benign polymorphism to our knowledge. Based on currently available evidence,we consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759267 SCV000888499 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000459323 SCV002580547 uncertain significance Colorectal cancer, susceptibility to, 12 2021-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002481391 SCV002794322 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 2021-08-25 criteria provided, single submitter clinical testing

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