Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenExperimental studies have shown that this variant affects ATM protein function (PMID: 27664052). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 22071889, 27664052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 870645). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 2627 of the ATM protein (p.Tyr2627His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATM protein function. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Pathogenic (1 clinical laboratories) and as Likely Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: ATMY2627HATMY2627HSomaticNCBI Gene:472|Show additional gene information Variant OverviewATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.The ATM Y2627H mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: ATM Y2627H does not lie within any known functional domains of the Atm protein (UniProt.org). Y2627H fails to rescue survival and proliferation of ATM-haploid cells upon olaparib treatment in a high-throughput cell culture assay (PMID: 40580951), and therefore, is predicted to lead to a loss of Atm protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -316 bp |
| Donor Loss (DL) | 0.01 | -31 bp |
| Acceptor Gain (AG) | 0.03 | -90 bp |
| Donor Gain (DG) | 0.01 | 48 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)