ATM c.7078T>G, p.Tyr2360Asp
NM_000051.4:c.7078T>G
Variant of Uncertain Significance (VUS)
This variant is classified as a Variant of Uncertain Significance because only PM2 (Supporting) and PP3 (Supporting) apply, and there is insufficient additional evidence to meet criteria for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PP3
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.7078T>G
Protein Change
Y2360D
Location
Exon 48
(Exon 48 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2360 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.7078T>G
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 2360 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.803
0.803
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: 5.12primateai: 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/finding for PVS1 is: "Use ATM PVS1 Decision Tree". The evidence for this variant shows: a missense change (Y2360D). Therefore, this criterion is not applied because PVS1 only applies to null variants (e.g., nonsense, frameshift, canonical ±1/2 splice sites) per the ATM-specific PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS1 is: "Use for protein changes as long as splicing is ruled-out for both alterations." The evidence for this variant shows: no previously established pathogenic variant resulting in the same amino acid change Y2360. Therefore, this criterion is not applied because there is no known pathogenic variant with the same amino acid substitution.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS3 is: "Use when a variant fails to rescue both an ATM-specific feature (e.g., phosphorylation of ATM-specific targets) AND radiosensitivity; do not use as strong; moderate/supporting strengths defined by specific functional assays." The evidence for this variant shows: no functional characterization in ATM-specific assays. Therefore, this criterion is not applied due to absence of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS4 is: "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5) for strong; moderate use is not for proband counting." The evidence for this variant shows: no case-control or cohort data. Therefore, this criterion is not applied due to lack of statistical association data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: "Located in a mutational hot spot and/or critical and well‐established functional domain without benign variation." The evidence for this variant shows: no evidence that Y2360 lies in a validated mutational hotspot or critical domain devoid of benign variation. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding for PM2 is: "Supporting Strength: Frequency ≤0.001% 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 (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is sufficiently rare/absent in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM3 is: "Use ATM PM3/BP2 table for recessive biallelic occurrences." The evidence for this variant shows: no evidence of biallelic occurrence or trans configuration in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM4 is: "Moderate Strength: Use for stop-loss variants." The evidence for this variant shows: a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM5 is: "Supporting Strength: Use for genomic frameshift and truncating variants or splice variants generating PTC upstream of p.Arg3047." The evidence for this variant shows: a missense substitution at Y2360. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no information on de novo status. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP1 is: "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data in familial cases. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and in which missense variants are a common mechanism of disease." The evidence for this variant shows: insufficient data on ATM gene-level missense constraint and benign variant rate. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting Strength: Protein: REVEL >0.7333; RNA: at least one well-established in silico predictor shows impact on splicing." The evidence for this variant shows: REVEL score 0.80 (>0.7333) and multiple in silico tools predict deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence supports a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: "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 or clinical presentation data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone Strength: Filtering Allele Frequency >0.5%." The evidence for this variant shows: absent from population databases (MAF=0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS1 is: "Strong Strength: Filtering Allele Frequency >0.05%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age." The evidence for this variant shows: no observations in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS3 is: "Moderate: variant rescues both an ATM-specific feature AND radiosensitivity; Supporting: rescues either one." The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: ATM is known to have pathogenic missense and truncating variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP2 is: "Use ATM PM3/BP2 table for evidence of allelic configuration." The evidence for this variant shows: no evidence of cis/trans configuration with another pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: a single nucleotide missense variant, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP4 is: "Supporting Strength: Protein Analysis: REVEL ≤0.249; RNA: at least one in silico predictor shows splice impact." The evidence for this variant shows: REVEL score 0.80 (>0.249) and no predicted splice defect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular cause for disease." The evidence for this variant shows: no information on alternative molecular diagnoses. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: not reported in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting: synonymous or deep intronic variants with no predicted impact on splicing." The evidence for this variant shows: a missense change, not synonymous. Therefore, this criterion is not applied.