Submissions for variant NM_014915.3(ANKRD26):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00021  dbSNP: rs199683454

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001106019	SCV001263043	benign	Thrombocytopenia 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV001655676	SCV001871121	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Identified in the germline of individuals with acute myeloid leukemia and/or persistent cytopenias referred for genetic testing at GeneDx and in published literature; however, some individuals harbored variants in other clinically relevant genes (PMID: 35295078, 36626254, 28100250); This variant is associated with the following publications: (PMID: 28100250, 32001092, 35295078, 36626254, 38493476)
Genetic Services Laboratory, University of Chicago	RCV001819815	SCV002065198	uncertain significance	not specified	2021-04-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ANKRD26 gene demonstrated a sequence change, c.3G>A, in exon 1 that is predicted to disrupt the translational state site. This sequence change does not appear to have been previously described in individuals with ANKRD26-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.052% in the non-Finnish European subpopulation (dbSNP rs199683454). The majority of pathogenic variants described to date in ANKRD26 occur in the 5'UTR region of this gene, and disrupts the binding of RUNX1 and FLI1 leading to an increased expression of ANKRD26 (PMIDs: 21211618, 24430186). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the c.3G>A change remains unknown at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001655676	SCV003284913	uncertain significance	not provided	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the ANKRD26 mRNA. The next in-frame methionine is located at codon 79. This variant is present in population databases (rs199683454, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. Disruption of the initiator codon has been observed in individual(s) with myelodysplastic syndrome (PMID: 35295078). ClinVar contains an entry for this variant (Variation ID: 878948). Studies have shown that disruption of the initiator codon alters ANKRD26 gene expression (PMID: 28100250). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetics and Molecular Pathology, SA Pathology	RCV001106019	SCV004175655	uncertain significance	Thrombocytopenia 2	2023-03-22	criteria provided, single submitter	clinical testing	The ANKRD26 c.3G>A variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (BS3) The ANKRD26 c.3G>A variant is a single nucleotide change which is predicted to result in loss of the start codon. Functional studies demonstrate that the variant results in the use of a downstream in-frame start codon and no effect on the protein function (PMID:28100250) (BS3). The variant has been reported in dbSNP (rs199683454) and as ?disease causing in the HGMD database (CM1727457). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 878948) and in population databases (gnomAD 30/152262 alleles, 0 hom, total allele frequency 0.019%). The variant has been detected in 2 patients with AML but not thrombocytopenia (PMID:28100250) as well as a child with inherited thrombocytopenia and myelodysplastic syndrome (PMID:35295078).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001106019	SCV005402419	uncertain significance	Thrombocytopenia 2	2024-02-23	criteria provided, single submitter	clinical testing	The ANKRD26 c.3G>A (p.Met1?) change results in a G>A substitution at nucleotide position 3 of exon 1 of the ANKRD26 gene. This change is predicted to result in the loss of the initiation codon. However, a downstream methionine exists, and a functional study supports the use of this downstream methionine (PMID: 28100250). This variant has a maximum subpopulation frequency of 0.05% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in individuals with acute myeloid leukemia and in an individual with thrombocytopenia and myelodysplastic syndrome (PMID: 28100250, 35295078). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.