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
OpenThe p.M563R variant (also known as c.1688T>G), located in coding exon 10 of the ATM gene, results from a T to G substitution at nucleotide position 1688. The methionine at codon 563 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This missense variant replaces methionine with arginine at codon 563 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28779002). This variant has been identified in 2/282688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
"This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.24 | -80 bp |
| Donor Loss (DL) | 0.15 | 114 bp |
| Acceptor Gain (AG) | 0.0 | 472 bp |
| Donor Gain (DG) | 0.0 | 0 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Use ATM PVS1 Decision Tree at Very Strong strength to evaluate null variants in ATM.' The evidence shows NM_000051.4:c.1688T>G is a missense variant (M563R), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Use for protein changes as long as splicing is ruled-out for both alterations.' The evidence shows M563R is a novel amino acid change not identical to any previously established pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' No de novo occurrence has been documented for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 is gene-specific and requires functional studies demonstrating a deleterious effect on ATM-specific features or radiosensitivity. No functional characterization exists for M563R. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Case-control studies; p-value ≤ .05 and odds ratio ≥ 2.' No case-control or proband frequency data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.' The position of M563R is not within a recognized functional domain or hot spot of ATM. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Frequency ≤ 0.001% if n=1 in a single sub population.' The variant has a frequency of 0.00401% in the African population and two alleles in gnomAD, exceeding the threshold. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive occurrences.' There is no evidence of this variant in trans with a pathogenic variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Use for stop-loss variants.' M563R does not result in stop-loss or protein length alteration. Therefore, this criterion is not applied.
PM5 (Supporting)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence shows a pathogenic missense variant previously reported at residue 563. Therefore, this criterion is applied at Supporting strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' No data suggest de novo occurrence. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variants and where missense is a common mechanism of disease.' ATM tolerates diverse missense variants and this criterion does not apply. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Protein: REVEL > 0.7333; RNA: at least one predictor shows impact.' The REVEL score is 0.07 and SpliceAI is low. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' No phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without evidence.' The variant is reported as VUS in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Allele frequency > 0.5%.' The variant frequency is 0.00401%, well below this threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Filtering Allele Frequency > 0.05%.' The frequency is 0.00401%, below this threshold. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age.' No such observation is reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Use when a variant rescues ATM-specific features.' No functional rescue data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family.' No segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease.' ATM has pathogenic missense variants; thus BP1 does not apply. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for recessive occurrences.' No evidence of trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive region without known function.' Not applicable to this missense variant. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Protein Analysis: Metapredictor REVEL score ≤ .249; RNA: at least one predictor shows impact.' The REVEL score is 0.07 and SpliceAI shows no impact. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' No such alternate basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without evidence.' No such report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no splicing impact.' The variant is missense. Therefore, this criterion is not applied.