ATM c.8520G>C, p.Leu2840Phe
NM_000051.4:c.8520G>C
COSMIC ID: COSM10346368
Variant of Uncertain Significance (VUS)
NM_000051.4:c.8520G>C (p.L2840F) in ATM is classified as Variant of Uncertain Significance because only PM2_supporting is met under VCEP guidelines, with no additional pathogenic or benign evidence.
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.8520G>C
Protein Change
L2840F
Location
Exon 58
(Exon 58 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2840 in gene ATM
Alternate Identifiers
COSM10346368
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.8520G>C
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
5 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
9 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
The ATM c.8520G>C (p.Leu2840Phe) variant has been reported in the published literature in a homozygous individual with ataxia telangiectasia who's biochemical evidence confirmed protein impairment (PMID: 22649200 (2012)). The frequency of this variant in the general population, 0.000013 (2/152098 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
The p.L2840F variant (also known as c.8520G>C), located in coding exon 57 of the ATM gene, results from a G to C substitution at nucleotide position 8520. The leucine at codon 2840 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in the homozygous state in an individual with a clinical diagnosis of ataxia-telangiectasia (Carney EF et al. J. Immunol., 2012 Jul;189:261-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2840 of the ATM protein (p.Leu2840Phe). This variant is present in population databases (rs752652869, gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 22649200). ClinVar contains an entry for this variant (Variation ID: 221124). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 26896183). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
This missense variant replaces leucine with phenylalanine at codon 2840 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. This variant has been reported in the homozygous state in individuals affected with ataxia-telangiectasia (PMID: 22649200, 26896183). Cells derived from these individuals have shown no detectable kinase activity. This variant has been identified in 1/246018 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Uncertain Significance
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
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 2840 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.464
0.464
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
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 3.65metasvm: 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: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: NM_000051.4:c.8520G>C 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: 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." The evidence for this variant shows: p.Leu2840Phe is not a previously established pathogenic amino acid change. Therefore, this criterion is not applied because there is no known pathogenic variant with the same 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 information is available. 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) 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 for this variant shows: no functional assays evaluating ATM-specific features or radiosensitivity have been reported. 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: "Strong Strength: Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). Modification Type: General recommendation." The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied due to lack of case-control evidence.
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 functional domain without benign variation." The evidence for this variant shows: there is no evidence that p.Leu2840 is in a known mutational hot spot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: the rule for PM2 is: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply Modification Type: Gene-specific,Strength." The evidence for this variant shows: it is absent from population databases (gnomAD MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is extremely rare/absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM3 is: "Supporting Strength: Supporting Use ATM PM3/BP2 table Modification Type: Disease-specific,General recommendation,Gene-specific,Strength." The evidence for this variant shows: no evidence of trans occurrence with another pathogenic ATM variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM4 is: "Moderate Strength: Moderate Use for stop-loss variants. Modification Type: General recommendation,Gene-specific." The evidence for this variant shows: it is a missense change, not a stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM5 is: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting... Modification Type: Gene-specific,Strength." The evidence for this variant shows: it is a missense variant, not a frameshift or truncating change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PM6 is: "Unconfirmed de novo (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 in a gene definitively known to cause the disease." The evidence for this variant shows: no family 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 that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: there is insufficient data on benign vs. pathogenic missense rates in ATM to apply PP2. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP3 is: "Supporting Strength: Supporting Protein Analysis: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing. Modification Type: Gene-specific." The evidence for this variant shows: REVEL=0.46 (<0.7333) and SpliceAI=0.01 (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 phenotype or family history information is available. 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, but the evidence is not available for review." The evidence for this variant shows: ClinVar classifies it as VUS, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or ExAC." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: MAF=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 (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS3 (Moderate) is: "Moderate Strength: Moderate Use when a variant rescues both an ATM-specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Disease-specific,Gene-specific,Strength." 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 for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant 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 for which primarily truncating variants are known to cause disease." The evidence for this variant shows: ATM has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP2 is: "Supporting Strength: Supporting Use ATM PM3/BP2 table Modification Type: Disease-specific,General recommendation,Gene-specific,Strength." 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 for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a missense single nucleotide change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BP4 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." The evidence for this variant shows: REVEL=0.46 (>0.249) and SpliceAI=0.01 (no impact), failing the thresholds. 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 for this variant shows: no such alternate molecular basis. 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, but evidence is not available for review." The evidence for this variant shows: no reputable benign classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP7 is: "Synonymous variant for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the creation of a new splice site; the nucleotide is not highly conserved." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.