ATM c.1370G>T, p.Arg457Leu
NM_000051.3:c.1370G>T
Variant of Uncertain Significance (VUS)
NM_000051.3:c.1370G>T (R457L) in ATM is classified as a VUS. Only PM2_Supporting (rarity) and BP4_Supporting (benign computational evidence) apply under VCEP guidelines, yielding conflicting supporting evidence and insufficient data for further criteria.
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_000051.3:c.1370G>T
Protein Change
R457L
Location
Exon 10
(Exon 10 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 457 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.1370G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
Remaining individuals
0.0163%
Low Frequency
Global: 0.000796%
Remaining individuals: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251396Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251396 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0163%, 1/6136 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
10 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (10 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 457 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.169
0.169
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: 3.16polyphen_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 PVS1 Decision Tree, the rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: NM_000051.3:c.1370G>T is a missense change (R457L), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP PS1 guidelines, the rule for PS1 is: "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.". The evidence for this variant shows: there is no previously established pathogenic variant causing the same amino acid change (R457L). 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 and no family history". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP PS3 guidelines, the rule for PS3 (Moderate) is: "Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.". The evidence for this variant shows: no functional characterization data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP PS4 guidelines, the rule for PS4 (Strong) 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 or statistical association data are available. 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 and/or critical and well‐established functional domain without benign variation". The evidence for this variant shows: R457L is not in a recognized mutational hot spot or critical functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP PM2 guidelines, the rule for PM2_Supporting is: "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: MAF = 0.000796% overall, with n=1 allele in a single subpopulation. Therefore, this criterion is applied at Supporting strength because the variant is sufficiently rare as defined.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP PM3 guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive inheritance". The evidence for this variant shows: no data on a second pathogenic variant in trans. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP PM4 guidelines, the rule for PM4 (Moderate) is: "Use for stop-loss variants". The evidence for this variant shows: R457L is a missense variant, not a stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP PM5 guidelines, the rule for PM5 (Supporting) is: "Use for genomic frameshift and truncating variants with PTC upstream of p.R3047". The evidence for this variant shows: the variant is missense, not truncating. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data are available. 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 are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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 missense constraint and mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP PP3 guidelines, the rule for PP3 is: "Protein: REVEL >.7333; RNA: At least one well‐established in silico predictor shows impact on splicing". The evidence for this variant shows: REVEL = 0.17 (≤.249) and SpliceAI = 0.07 (no splicing impact). 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 disease with a single genetic etiology". The evidence for this variant shows: no phenotypic specificity data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic". The evidence for this variant shows: ClinVar reports Uncertain Significance. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP BA1 guidelines, the rule for BA1 is: "Filtering Allele Frequency >.5%". The evidence for this variant shows: MAF = 0.000796% (<.5%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP BS1 guidelines, the rule for BS1 is: "Filtering Allele Frequency >.05%". The evidence for this variant shows: MAF = 0.000796% (<.05%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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 healthy adult data available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP BS3 guidelines, the rule for BS3 (Moderate) is: "Use when a variant rescues both an ATM specific feature AND radiosensitivity". The evidence for this variant shows: no functional rescue data available. 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 members of a family". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule 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 has pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP BP2 guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table for allelic observations in cis". The evidence for this variant shows: no cis/trans data available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in repetitive regions without known function". The evidence for this variant shows: R457L is a single nucleotide missense change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP BP4 guidelines, the rule for BP4 is: "Protein Analysis: Metapredictor REVEL score ≤.249; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence for this variant shows: REVEL = 0.17 (≤.249) and SpliceAI = 0.07 (no splicing impact). Therefore, this criterion is applied at Supporting strength because computational evidence predicts no functional impact.
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 basis for disease". The evidence for this variant shows: no alternate molecular diagnosis provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign". The evidence for this variant shows: ClinVar reports Uncertain Significance, not benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP BP7 guidelines, the rule for BP7 is: "Use for synonymous and deep intronic variants defined as further than +7/-40 from splice sites". The evidence for this variant shows: R457L is a missense change. Therefore, this criterion is not applied.