ATM c.8161G>A, p.Asp2721Asn
NM_000051.4:c.8161G>A
COSMIC ID: COSM200673, COSM2110634
Variant of Uncertain Significance (VUS)
The variant NM_000051.4:c.8161G>A (p.D2721N) remains a VUS. It is absent from population databases (PM2_supporting), has strong computational support for deleterious effect (PP3_supporting), and a single likely pathogenic report in ClinVar (PP5_supporting). No functional, segregation, or case-control data are available to meet higher‐level criteria for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PP3
PP5
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.8161G>A
Protein Change
D2721N
Location
Exon 56
(Exon 56 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2721 in gene ATM
Alternate Identifiers
COSM200673, COSM2110634
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.8161G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The p.D2721N variant (also known as c.8161G>A), located in coding exon 55 of the ATM gene, results from a G to A substitution at nucleotide position 8161. The aspartic acid at codon 2721 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in two individuals with ataxia telangectasia, each of whom also harbored a truncating mutation in ATM. Both individuals exhibited severe ataxia, neuropathy, ocular motor abnormalities, telangiectasias, elevated AFP, and other features of A-T; however, age of onset was slightly later than typical A-T, at 7 years and 8 years, respectively (Méneret A et al. Neurology, 2014 Sep;83:1087-95). Méneret et al. also performed functional analyses on patient lymphoblastoid cell lines and found 37% of wild-type ATM product via Western blotting and only 5% of wild-type ATM kinase activity. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2721 of the ATM protein (p.Asp2721Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 21665257, 25122203). ClinVar contains an entry for this variant (Variation ID: 1054111). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. 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.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 2721 in gene ATM
Functional Summary
The ATM D2721N variant has not been functionally characterized, and its effect on ATM protein function is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.957
0.957
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 6.17primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows: it is a missense change (D2721N), not a null variant. Therefore, this criterion is not applied at Not Applied strength because missense variants do not meet PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: 'Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations.' The evidence for this variant shows: D2721N is not the same amino acid change as any previously established pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because there is no identical amino acid change previously established as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status is not documented.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'Moderate Strength: Moderate Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity'. The evidence for this variant shows: no functional studies of ATM D2721N are available. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been experimentally evaluated.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: 'Strong Strength: Case-control studies; p-value ≤ .05 AND (Odds ratio ≥ 2 OR lower 95% CI ≥ 1.5)'. The evidence for this variant shows: no case-control data are reported. Therefore, this criterion is not applied at Not Applied strength because statistical association data are lacking.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Located in a mutational hot spot and/or critical and well-established functional domain without benign variation'. The evidence for this variant shows: domain mapping of D2721N within ATM critical domains was not specifically provided. Therefore, this criterion is not applied at Not Applied strength because there is insufficient evidence that D2721 lies in a defined critical domain hot spot.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'Supporting Strength: Frequency ≤ .001% if n=1 in a single subpopulation, that is sufficiently rare and PM2_supporting would apply'. The evidence for this variant shows: absent from gnomAD (n=0). Therefore, this criterion is applied at Supporting strength because the variant is essentially absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: 'Very Strong/Strong/Moderate/Supporting Strength: Use ATM PM3/BP2 table'. The evidence for this variant shows: no data on trans or compound heterozygosity in an autosomal recessive context. Therefore, this criterion is not applied at Not Applied strength because PM3 evidence is not available.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: 'Moderate Strength: Use for stop-loss variants'. The evidence for this variant shows: D2721N is a missense change, not a stop-loss. Therefore, this criterion is not applied at Not Applied strength because the variant does not alter stop codons.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: 'Supporting Strength: Use for frameshift and truncating variants with PTC upstream of p.R3047'. The evidence for this variant shows: D2721N is a missense change, not truncating. Therefore, this criterion is not applied at Not Applied strength because PM5 applies only to premature termination codon variants.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Assumed de novo, without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied at Not Applied strength because there is no evidence of de novo occurrence.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied at Not Applied strength because family segregation has not been evaluated.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Missense variant in a gene with low rate of benign missense variation and pathogenic missense variants common'. The evidence for this variant shows: ATM has both benign and pathogenic missense variation; specificity is unclear. Therefore, this criterion is not applied at Not Applied strength because gene-level missense constraint was not established.
PP3
PP3 (Supporting)
According to VCEP guidelines: 'Supporting Strength: Protein: REVEL > .7333'. The evidence for this variant shows: REVEL score is 0.96. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a deleterious effect and REVEL exceeds the threshold.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied at Not Applied strength because clinical specificity is not documented.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: 'Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation'. The evidence for this variant shows: ClinVar includes one laboratory classification of Likely Pathogenic. Therefore, this criterion is applied at Supporting strength because a reputable database reports it as likely pathogenic without accessible primary data.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Allele frequency is > 5% in control populations'. The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because frequency is far below the threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied at Not Applied strength because frequency is not elevated.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Observed in healthy adult individuals for a dominant disorder with full penetrance'. The evidence for this variant shows: no healthy adult carrier data. Therefore, this criterion is not applied at Not Applied strength because no such observations are reported.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: 'Moderate Strength: Use when a variant rescues both an ATM specific feature AND radiosensitivity'. The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied at Not Applied strength because experimental rescue has not been assessed.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Lack of segregation in affected members of a family'. The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied at Not Applied strength because absence of segregation data does not meet BS4.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Missense variant in a gene for which primarily truncating variants cause disease'. The evidence for this variant shows: ATM disease mechanism includes both missense and truncating variants. Therefore, this criterion is not applied at Not Applied strength because ATM is not strictly loss-of-function only.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: 'Use ATM PM3/BP2 table'. The evidence for this variant shows: no evidence of cis/trans observations that would support benign interpretation. Therefore, this criterion is not applied at Not Applied strength because BP2 evidence is not present.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'In-frame deletions/insertions in repetitive region without known function'. The evidence for this variant shows: D2721N is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because BP3 is not relevant.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: 'Supporting Strength: Protein Analysis: REVEL score ≤ .249'. The evidence for this variant shows: REVEL is 0.96, above the benign threshold. Therefore, this criterion is not applied at Not Applied strength because computational evidence supports pathogenicity, not benignity.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no alternate cause reported. Therefore, this criterion is not applied at Not Applied strength because no such context exists.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Reputable source reports variant as benign, but evidence not available'. The evidence for this variant shows: no benign expert classification in ClinVar. Therefore, this criterion is not applied at Not Applied strength because no such source exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: 'Synonymous variant with no predicted impact on splicing and low nucleotide conservation'. The evidence for this variant shows: D2721N is missense. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.