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 ↗

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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