ATM c.8998C>G, p.Gln3000Glu
NM_000051.4:c.8998C>G
Variant of Uncertain Significance (VUS)
Q3000E is absent from population databases (PM2_supporting) and computational evidence strongly favors no impact (BP4_supporting). No additional pathogenic or benign evidence is available, resulting in a final classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.8998C>G
Protein Change
Q3000E
Location
Exon 63
(Exon 63 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3000 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
Loading genome browser...
HGVS InputNM_000051:c.8998C>G
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
1 publications
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
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.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 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 3000 in gene ATM
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.42metasvm: 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 PVS1 rule is: "Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows that Q3000E is a missense change and does not create a null allele. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule is: "Strong Strength: Strong Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. Modification Type: General recommendation". The evidence shows no previously established pathogenic variant resulting in Q3000E. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS2 rule is: "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, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the PS3 rule is: "Moderate Strength: Moderate Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Gene-specific,Strength". The evidence shows that no functional studies have been performed for Q3000E. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS4 rule is: "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5)". The evidence for this variant shows no case-control data. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM1 rule is: "Located in a mutational hot spot and/or critical functional domain without benign variation". The evidence shows Q3000 is not in a known mutational hotspot or critical domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule is: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply". The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the PM3 rule is: "Very Strong Strength: Very Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength". The evidence for this variant shows no information on allele phase or recessive inheritance in trans with a pathogenic variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule is: "Protein length changes due to in‐frame deletions/insertions in a non-repeat region". The evidence shows Q3000E does not change protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the PM5 rule is: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...". The evidence shows Q3000E is a missense change with no other pathogenic missense at the same residue. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows no de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP1 rule is: "Co-segregation with disease in multiple affected family members". The evidence shows no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence shows ATM has both LOF and missense pathogenic variants and tolerance to some missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the PP3 rule is: "Supporting Strength: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence shows benign or mixed computational predictions and SpliceAI score 0.03. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP4 rule is: "Patient’s phenotype or family history is highly specific for a gene". The evidence shows no phenotype information. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP5 rule is: "Reputable source recently reports variant as pathogenic without available evidence". The evidence shows ClinVar entries are VUS or Likely Benign, not Pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the BA1 rule is: "Stand Alone Strength: Stand Alone Filtering Allele Frequency >.5%". The evidence shows allele frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the BS1 rule is: "Strong Strength: Strong Filtering Allele Frequency >.05%". The evidence shows allele frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS2 rule is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence shows no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the BS3 rule is: "Moderate Strength: Moderate Use when a variant rescues both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity". The evidence shows no functional rescue data. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS4 rule is: "Lack of segregation in affected members". The evidence shows no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP1 rule is: "Missense variant in a gene for which primarily truncating variants are known to cause disease". The evidence shows missense variants in ATM can be pathogenic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the BP2 rule is: "Strong Strength: Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength". The evidence shows no evidence of this variant in trans with a pathogenic variant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule is: "In-frame deletions/insertions in a repetitive region without a known function". The evidence shows Q3000E is not an in-frame indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the BP4 rule is: "Supporting Strength: Supporting Protein Analysis: Metapredictor REVEL score ≤.249 RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing NOTE: Splice analysis needs to be considered for all variant types...". The evidence shows multiple benign computational predictions and SpliceAI score 0.03. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule is: "Variant found in a case with an alternate molecular basis for disease". The evidence shows no alternate molecular diagnosis. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign without available evidence". The evidence shows no such expert benign assertion. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP7 rule is: "Synonymous variant for which splicing prediction algorithms predict no impact". The evidence shows Q3000E is a missense change. Therefore, BP7 is not applied.