ATM c.2618G>A, p.Gly873Glu
NM_000051.4:c.2618G>A
Variant of Uncertain Significance (VUS)
The ATM c.2618G>A (p.G873E) missense variant is absent from population databases (PM2_supporting) but lacks additional pathogenic or benign evidence. No functional, segregation, or phenotypic specificity data are available. Applying only PM2_supporting yields a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.2618G>A
Protein Change
G873E
Location
Exon 17
(Exon 17 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 873 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.2618G>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
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 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 873 in gene ATM
Functional Summary
The ATM G873E variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.265
0.265
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: 2.96polyphen_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: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows it is a missense change (G873E) without predicted splicing impact and not a null/truncating variant. Therefore, this criterion is Not Applied because the variant is not a predicted loss-of-function event.
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 shows no previously established pathogenic variant resulting in the same amino acid change at position 873. Therefore, PS1 is Not Applied.
PS2
PS2 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There is no available de novo segregation data for this variant. Therefore, PS2 is Not Applied.
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; Supporting Strength: Use when a variant fails to rescue an ATM specific feature only." No functional studies characterizing G873E in ATM are available. Therefore, PS3 is Not Applied due to lack of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PS4: The prevalence of the variant in affected individuals is significantly increased compared with controls (case-control data)." No case-control or proband counting data are available. Therefore, PS4 is Not Applied.
PM1
PM1 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PM1: Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The variant lies outside known ATM mutational hotspots or critical domains. Therefore, PM1 is Not Applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply." The evidence shows the variant is absent from gnomAD (MAF = 0%). Therefore, PM2 is Applied at Supporting strength because the allele frequency is below the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "Use ATM PM3/BP2 table" for trans observations in recessive cases. No data on trans configuration with pathogenic variants exist. Therefore, PM3 is Not Applied.
PM4
PM4 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PM4: Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss." This is a missense variant without protein length change. Therefore, PM4 is Not Applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; apply also to splice variants under specific conditions." This variant is missense and does not meet splice-based criteria. Therefore, PM5 is Not Applied.
PM6
PM6 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PM6: Assumed de novo, but without confirmation of paternity/maternity." There is no de novo data. Therefore, PM6 is Not Applied.
PP1
PP1 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PP1: Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, PP1 is Not Applied.
PP2
PP2 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PP2: Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." ATM has both benign and pathogenic missense variants. Therefore, PP2 is Not Applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Protein Analysis: REVEL >.7333; RNA: at least one well-established in silico predictor shows impact on splicing." The REVEL score is 0.27 (<0.7333) and SpliceAI shows no splicing impact. Therefore, PP3 is Not Applied.
PP4
PP4 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype specificity data are provided. Therefore, PP4 is Not Applied.
PP5
PP5 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "PP5: Reputable source recently reports variant as pathogenic." ClinVar entries report this variant as VUS. Therefore, PP5 is Not Applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone Strength: Filtering Allele Frequency >.5%." The variant frequency is 0%. Therefore, BA1 is Not Applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong Strength: Filtering Allele Frequency >.05%." The allele frequency is 0%. Therefore, BS1 is Not Applied.
BS2
BS2 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BS2: Observed in a healthy adult individual for a dominant disorder with full penetrance." No such healthy adult observations are reported. Therefore, BS2 is Not Applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate Strength: Use when a variant rescues both an ATM specific feature AND radiosensitivity; Supporting Strength: Use when a variant rescues either feature." No rescue functional data are available. Therefore, BS3 is Not Applied.
BS4
BS4 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BS4: Lack of segregation in affected members of a family." No segregation data are available. Therefore, BS4 is Not Applied.
BP1
BP1 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BP1: Missense variant in a gene where only truncating variants cause disease." ATM has pathogenic missense variants. Therefore, BP1 is Not Applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Use ATM PM3/BP2 table" for cis/trans observations. No such observations exist. Therefore, BP2 is Not Applied.
BP3
BP3 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BP3: In-frame deletions/insertions in repetitive regions without impact." This is a missense variant, not an in-frame indel. Therefore, BP3 is Not Applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting Strength: Protein Analysis: REVEL score ≤.249; RNA: at least one predictor shows impact on splicing." The REVEL score is 0.27 (>0.249) and SpliceAI shows no splicing impact. Therefore, BP4 is Not Applied.
BP5
BP5 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BP5: Variant found in a case with an alternate molecular basis for disease." No such alternate findings are reported. Therefore, BP5 is Not Applied.
BP6
BP6 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BP6: Reputable source reports variant as benign without available evidence." No such reports are available. Therefore, BP6 is Not Applied.
BP7
BP7 (Not Applied) Strength Modified
According to Standard ACMG guidelines: "BP7: Synonymous variant with no predicted impact on splicing and low conservation." This is a missense variant. Therefore, BP7 is Not Applied.