ATM c.3758A>G, p.Lys1253Arg
NM_000051.4:c.3758A>G
COSMIC ID: COSM5413302
Variant of Uncertain Significance (VUS)
The ATM c.3758A>G (p.K1253R) variant remains classified as a Variant of Uncertain Significance because only PM2 (Supporting) and BP4 (Supporting) are met, with no additional strong pathogenic or benign evidence.
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.3758A>G
Protein Change
K1253R
Location
Exon 26
(Exon 26 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1253 in gene ATM
Alternate Identifiers
COSM5413302
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.3758A>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
1 publications
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The p.K1253R variant (also known as c.3758A>G), located in coding exon 25 of the ATM gene, results from an A to G substitution at nucleotide position 3758. The lysine at codon 1253 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (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 1253 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.191
0.191
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: 4.10polyphen_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 standard ACMG guidelines, the rule for PVS1 is: 'Null Variant (nonsense, frameshift, 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: c.3758A>G (p.K1253R) is a missense change, not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant requirement.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: no previously established pathogenic variant at residue Lys1253. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
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 evidence has been reported. 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 for PS3 (Moderate Strength) 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 studies assessing ATM-specific feature rescue have been performed. Therefore, this criterion is not applied because functional evidence is missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Case-control studies; p-value ≤.05 AND (Odds ratio ≥2 OR lower 95% CI ≥1.5)'. The evidence for this variant shows: no case-control data 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: Lys1253 is not in a known mutational hotspot or critical functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: 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: absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength due to the variant's absence in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: no evidence of compound heterozygosity or homozygosity with another pathogenic ATM variant. 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 due to in-frame deletions/insertions in a non-repeat region or stop-loss variants'. The evidence for this variant shows: missense change without affecting protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; apply to splice variants carrying PTC upstream of p.Arg3047'. The evidence for this variant shows: missense change. 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 assumption has been made. 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 in a gene definitively known to cause the disease'. The evidence for this variant shows: no segregation data 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 low rate of benign missense variation'. The evidence for this variant shows: ATM has many missense variants observed, so low rate of benign missense variation is not established. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing'. The evidence for this variant shows: REVEL score 0.19 and SpliceAI max score 0.1 indicating no predicted 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 highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history 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 reports variant as pathogenic'. The evidence for this variant shows: ClinVar entry is Uncertain Significance, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: Filtering Allele Frequency >.5%'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: Filtering Allele Frequency >.05%'. The evidence for this variant shows: allele frequency is 0%. 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'. The evidence for this variant shows: no healthy adult observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Moderate Strength: Use when a variant rescues both an ATM specific feature and radiosensitivity; Supporting Strength: Use when a variant rescues either feature or radiosensitivity'. The evidence for this variant shows: no functional rescue studies performed. 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 cause disease'. The evidence for this variant shows: ATM pathogenic alleles include both truncating and missense; the variant is missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for observations in trans with a pathogenic variant'. The evidence for this variant shows: no evidence of trans configuration with a pathogenic variant. 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 a repetitive region without a functional impact'. The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: 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 score 0.19 and SpliceAI max score 0.1 indicating no impact on splicing. Therefore, this criterion is applied at Supporting strength due to benign computational predictions.
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 reported. 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 variant as benign'. The evidence for this variant shows: ClinVar lists this variant as Uncertain Significance. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous (silent) variant with no impact on splicing predicted'. The evidence for this variant shows: it is a missense variant, not synonymous. Therefore, this criterion is not applied.