Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis missense variant replaces asparagine with serine at codon 778 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast, pancreatic and ovarian cancers (PMID: 20305132, 25186627, 25479140, 26689913, 29522266). This variant has been identified in 3/251370 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.
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 778 of the ATM protein (p.Asn778Ser). This variant is present in population databases (rs587779820, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic cancer (PMID: 20305132, 25186627, 25479140, 26689913). ClinVar contains an entry for this variant (Variation ID: 127348). 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%. 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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Variant summary: ATM c.2333A>G (p.Asn778Ser) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 1.2e-05 in 251371 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2333A>G has been observed in individual(s) affected with breast, ovarian, or pancreatic cancer without strong evidence for causality (Bernstein_2010, Grant_2015, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 25479140, 25186627). ClinVar contains an entry for this variant (Variation ID: 127348). Based on the evidence outlined above, the variant was classified as uncertain significance.
"This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 82 bp |
| Donor Loss (DL) | 0.0 | 199 bp |
| Acceptor Gain (AG) | 0.04 | -63 bp |
| Donor Gain (DG) | 0.02 | 43 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
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: it is a missense change (N778S) not predicted to cause loss of function. Therefore, this criterion is not applied because the variant does not meet the VCEP-defined loss-of-function mechanism required for PVS1.
PS1 (Not Applied)
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: there is no previously established pathogenic variant with the same amino acid change. Therefore, PS1 is not applied.
PS2 (Not Applied)
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 data on de novo occurrence. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "**Strong Strength**: Strong Do not use as strong. Modification Type: Gene-specific". The evidence for this variant shows: no functional assays have been performed for N778S. Therefore, PS3 is not applied.
PS4 (Not Applied)
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).". The evidence for this variant shows: no case-control or cohort data. Therefore, PS4 is not applied.
PM1 (Not Applied)
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: N778S is not located in a known ATM mutational hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Not Applied)
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. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply.". The evidence for this variant shows: MAF=0.00264% in the European (non-Finnish) population with n=3. Therefore, PM2 is not applied because the allele frequency exceeds the VCEP threshold and n>1.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "**Very Strong Strength**: Very Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength". The evidence for this variant shows: no data on trans configuration in an individual with a second pathogenic ATM variant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "**Moderate Strength**: Moderate Use for stop-loss variants.". The evidence for this variant shows: N778S is a missense variant, not a stop-loss. Therefore, PM4 is not applied.
PM5 (Not Applied)
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...". The evidence for this variant shows: it is a missense change, not a frameshift or truncating variant. Therefore, PM5 is not applied.
PM6 (Not Applied)
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. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation 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. Therefore, PP1 is not applied.
PP2 (Not Applied)
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 in which missense variants are a common mechanism of disease.". The evidence for this variant shows: ATM pathogenic mechanisms are primarily loss-of-function rather than missense. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "**Supporting Strength**: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing.". The evidence for this variant shows: SpliceAI score=0.04 (no splicing impact) and computational tools predominantly predict benign. Therefore, PP3 is not applied.
PP4 (Not Applied)
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 data. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic or likely pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar reports VUS and Likely Benign, but no pathogenic assertions. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "**Stand Alone Strength**: Stand Alone Filtering Allele Frequency >.5%.". The evidence for this variant shows: MAF <<0.5%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "**Strong Strength**: Strong Filtering Allele Frequency >.05%.". The evidence for this variant shows: MAF=0.00264% <<0.05%. Therefore, BS1 is not applied.
BS2 (Not Applied)
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 data on observation in healthy adults. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "**Moderate Strength**: Moderate Use when a variant rescues both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity; **Supporting Strength**: Supporting Use when a variant rescues either feature.". The evidence for this variant shows: no functional rescue data. Therefore, BS3 is not applied.
BS4 (Not Applied)
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, BS4 is not applied.
BP1 (Not Applied)
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 does have some pathogenic missense variants. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "**Strong Strength**: Strong Use ATM PM3/BP2 table.". The evidence for this variant shows: no data on cis/trans observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
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 single amino acid substitution. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "**Supporting Strength**: Supporting Protein Analysis: Metapredictor REVEL score ≤.249; RNA: At least one predictor (e.g. SpliceAI) shows impact on splicing.". The evidence for this variant shows: SpliceAI predicts no splicing impact and REVEL score unavailable but other predictors mixed. Therefore, BP4 is not applied.
BP5 (Not Applied)
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 case data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports as benign, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar contains conflicting VUS and Likely Benign assertions. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "**Supporting Strength**: Supporting Can be considered for BP7_(RNA) with curator discretion of quality; use for synonymous and deep intronic variants.". The evidence for this variant shows: it is missense, not synonymous or deep intronic. Therefore, BP7 is not applied.