ATM c.5509T>G, p.Phe1837Val
NM_000051.4:c.5509T>G
Variant of Uncertain Significance (VUS)
The variant F1837V in ATM is absent from population databases (PM2_supporting) but lacks additional evidence of pathogenicity or benign impact. Per VCEP-specified thresholds, only PM2_supporting can be applied, resulting in a classification of VUS.
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.5509T>G
Protein Change
F1837V
Location
Exon 37
(Exon 37 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1837 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.5509T>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
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
6 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 (6 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 1837 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.321
0.321
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: 3.66polyphen_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, 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 shows: NM_000051.4:c.5509T>G is a missense variant, not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant definition.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, as long as splicing is ruled-out. The evidence shows: No previously established pathogenic variant at codon F1837. Therefore, this criterion is not applied due to lack of a known pathogenic amino acid match.
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 shows: No de novo data available. Therefore, this criterion is not applied due to absence of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: Use when a variant fails to rescue both an ATM specific feature and radiosensitivity (Strong) or other defined thresholds. The evidence shows: No functional studies available for F1837V. Therefore, this criterion is not applied because functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: Case-control studies with p≤0.05 AND odds ratio ≥2 (lower 95% CI ≥1.5). The evidence shows: No case-control data or case series. 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 for PM1 is: Located in a mutational hot spot or well-established functional domain without benign variation. The evidence shows: No information that F1837 lies in a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: Frequency ≤.001% if n=1 in a single subpopulation (PM2_supporting). The evidence shows: Variant absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the allele frequency meets the rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: Evidence of trans-occurrence with a pathogenic variant in a recessive disorder (strength per table). The evidence shows: No data on compound heterozygosity or trans variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: Use for stop-loss variants (Moderate). The evidence shows: F1837V is not a stop-loss variant. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: Novel missense change at a residue with a different pathogenic missense change (Supporting). The evidence shows: No other missense pathogenic variants reported at residue F1837. 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 without confirmation of paternity/maternity. The evidence shows: No de novo or family data. 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 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 variants where missense is a common mechanism of disease. The evidence shows: ATM has many reported pathogenic and benign missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: REVEL >0.7333 or RNA impact. The evidence shows: REVEL score is 0.32 and SpliceAI predicts no impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: Patient phenotype highly specific for a disease with a single genetic etiology. The evidence shows: Clinical phenotype data not 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 shows: ClinVar lists this variant as VUS. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: Allele frequency >0.5%. The evidence shows: Variant is absent. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: Allele frequency >0.05%. The evidence shows: Variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: Observed in healthy adult with full penetrance expectation. The evidence shows: No such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: Functional studies show rescue of ATM features. The evidence shows: No functional rescue data. 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 or segregation in unaffected. The evidence shows: No segregation data. 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 where only truncating variants cause disease. The evidence shows: Pathogenic missense variants are known in ATM. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: Observed in trans with a pathogenic variant in recessive context. The evidence shows: No data on trans phase. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: In-frame indel in repetitive region without known function. The evidence shows: Variant is missense. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: REVEL ≤0.249 or at least one RNA predictor shows impact. The evidence shows: REVEL is 0.32 and SpliceAI shows no impact. Therefore, this criterion is not applied.
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 shows: No such data. 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 without shared evidence. The evidence shows: ClinVar lists VUS. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: Synonymous or deep intronic variant with no splicing impact. The evidence shows: Variant is missense. Therefore, this criterion is not applied.