Classification rationale

PM2PP3 VUS

ATM c.2930G>A

The ATM c.2930G>A (p.Cys977Tyr; p.C977Y) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic, although at least one submission classifies it as uncertain significance.¹ This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 0.00025% (4/1,609,362 alleles) and gnomAD v2.1 showing 0.00340% (1/29,448 alleles), which is below the ATM PM2_Supporting threshold of 0.001%.² Computational evidence supports a damaging missense effect, with REVEL 0.778 above the ATM PP3 threshold of 0.7333 and BayesDel 0.318994, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.02.³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 revelbayesdelspliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 11 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is very rare in population databases. In gnomAD v4.1 the total allele frequency is 0.00025% (4/1,609,362 alleles) and the highest observed subpopulation frequency is 0.00034%, both below the ATM PM2_Supporting threshold of 0.001%.

gnomAD v4.1 total AF 2.4854569699048445e-06gnomAD v4.1 highest subpopulation AF 3.393344633170962e-06gnomAD v2.1 total AF 3.395816354251562e-05

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

PP3 supporting review Pathogenic

Computational evidence supports a deleterious missense effect. The REVEL score is 0.778, which is above the ATM PP3 threshold of 0.7333, and BayesDel is 0.318994. SpliceAI predicts no significant splice impact (max delta score 0.02), so the supporting computational evidence is for missense effect rather than splice disruption.

REVEL score 0.778BayesDel score 0.318994SpliceAI max delta score 0.02

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 7 not assessed

Pathogenic

PVS1 This is a missense variant, not a predicted null variant, and the ATM PVS1 framework is intended for loss-of-function events.

PS1 ATM PS1 can be used for a missense change when a different nucleotide change is already established as pathogenic or likely pathogenic for the same amino acid substitution and splicing is ruled out.

PS3 ATM PS3 requires variant-specific functional studies showing failure to rescue an ATM-specific feature, with stronger weight requiring failure to rescue both an ATM-specific feature and radiosensitivity.

PS4 ATM PS4 requires case-control evidence with p-value 0.05 or less and effect size at least 2.

PM3 ATM PM3 requires observations in trans with a pathogenic variant in individuals with ataxia-telangiectasia and scoring by the ATM PM3/BP2 point framework.

PP1 ATM PP1 in this framework requires segregation in affected relatives for the recessive ataxia-telangiectasia phenotype.

Benign

BA1 This variant does not meet the ATM BA1 threshold.

BS1 This variant does not meet the ATM BS1 threshold.

BS3 ATM BS3 requires variant-specific functional studies showing rescue of both an ATM-specific feature and radiosensitivity for moderate weight, or rescue of either for supporting weight.

BP2 ATM BP2 requires co-occurrence or homozygosity evidence scored through the ATM PM3/BP2 framework in unaffected or non-ataxia-telangiectasia settings.

BP4 Benign computational evidence is not supported.

N/A · 15 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.48546e-06; MAF= 0.00025%, 4/1609362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39334e-06; MAF= 0.00034%, 4/1178778 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.39582e-05; MAF= 0.00340%, 1/29448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.9185e-05; MAF= 0.00692%, 1/14454 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00025% · 4 / 1,609,362
0 hom · FAF 7.9e-05%

European (non-Finnish)

4 / 1,178,778

0.00034%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0034% · 1 / 29,448
0 hom

European (non-Finnish)

1 / 14,454

0.0069%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory). (ClinVarID = 233765)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.778. BayesDel score = 0.318994.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53734070, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

31317629 ↗ Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests. CLINVAR

34445196 ↗ NGS in Hereditary Ataxia: When Rare Becomes Frequent. CLINVAR

35047863 ↗ A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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