ATM c.5410A>T, p.Ile1804Phe
NM_000051.4:c.5410A>T
Variant of Uncertain Significance (VUS)
This ATM missense variant (I1804F) is classified as VUS because only one benign-supporting criterion (BP4) is met under VCEP guidelines, with no moderate or strong pathogenic or benign criteria applicable.
ACMG/AMP Criteria Applied
BP4
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.5410A>T
Protein Change
I1804F
Location
Exon 36
(Exon 36 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1804 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.5410A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00199%
Rare
Highest in Population
Remaining individuals
0.0163%
Low Frequency
Global: 0.00199%
Remaining individuals: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251146Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00199%, 5/251146 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0163%, 1/6120 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
6 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1804 of the ATM protein (p.Ile1804Phe). This variant is present in population databases (rs769872474, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 19781682, 28779002, 29596542, 34326862). ClinVar contains an entry for this variant (Variation ID: 219462). 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 not expected to disrupt ATM protein function with a negative 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 (6 clinical laboratories) and as Likely benign (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 1804 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.054
0.054
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
No
Additional Predictors
Benign:
CADD: -0.37polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: use the ATM PVS1 Decision Tree; PVS1 applies only to null variants in ATM where LOF is a known mechanism. The evidence for this variant shows it is a missense change (I1804F), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: same amino acid change as a previously established pathogenic variant. The evidence for this variant shows no previously established pathogenic variant results in I1804F. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: de novo (both maternity and paternity confirmed) in a patient with the disease. The evidence for this variant shows no de novo data or parental testing. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: functional studies showing failure to rescue ATM-specific features (phosphorylation AND radiosensitivity) for Strong or only phosphorylation for Supporting. The evidence for this variant shows no functional characterization. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: case-control studies with p≤.05 and OR≥2 (or lower 95% CI≥1.5). The evidence for this variant shows no case-control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: located in a mutational hot spot or well-studied functional domain without benign variation. The evidence for this variant shows no known hotspot or domain-specific enrichment. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2_Supporting is: frequency ≤0.001% if n=1 in a single subpopulation. The evidence for this variant shows MAF=0.00199% with n=5 in gnomAD. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: detected in trans with a pathogenic variant for recessive disorders. The evidence for this variant shows no phasing or trans data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: protein length changes (in-frame indels or stop-loss). The evidence for this variant shows a missense substitution with no length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5_Supporting is: novel missense at an amino acid where a different pathogenic missense has been seen. The evidence for this variant shows no other pathogenic change at I1804. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: presumed de novo without confirmation of paternity/maternity. The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: co-segregation with disease in multiple affected family members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: missense in a gene with low rate of benign missense or where missense is common mechanism. ATM has known pathogenic and benign missense; no evidence support. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: protein computational evidence REVEL>0.733 or RNA splicing impact. The evidence for this variant shows REVEL=0.05 and SpliceAI=0.01. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: patient’s phenotype or family history is highly specific for a gene. The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: reputable source reports as pathogenic. The evidence for this variant shows ClinVar entries as VUS or likely benign only. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: allele frequency >0.5%. The evidence for this variant shows MAF=0.00199%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: allele frequency >0.05%. The evidence for this variant shows MAF=0.00199%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: observed in healthy adult individuals with full penetrance. The evidence for this variant shows no data from healthy adults. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: functional studies showing rescue of ATM-specific features. The evidence for this variant shows no functional data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: lack of segregation in affected family members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: missense in a gene where only truncating variants cause disease. The evidence for this variant shows ATM has known pathogenic missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: observed in cis with a pathogenic variant. The evidence for this variant shows no phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: in-frame indel in repetitive region without functional impact. The evidence for this variant shows a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: REVEL≤0.249 or splicing impact minimal. The evidence for this variant shows REVEL=0.05 and SpliceAI=0.01. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: variant found in a case with an alternate molecular cause. The evidence for this variant shows no such context. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: reputable source reports as benign. The evidence for this variant shows no such report used. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: synonymous or deep intronic variant with no splicing impact. The evidence for this variant shows a missense change. Therefore, this criterion is not applied.