Classification rationale

PM2 BP4 VUS

ATM c.838A>G

PM2 (Supporting): gnomAD v4.1 total allele frequency 0.000186% (3/1,613,222 alleles) is below the 0.001% threshold, confirming the variant is extremely rare. BP4 (Supporting): REVEL 0.043 is well below the 0.249 missense threshold, indicating a benign-leaning computational effect. Final: PM2 supporting (pathogenic side) combined with BP4 supporting (benign side) satisfies the conflicting-evidence rule, giving VUS (uncertain significance).

PM2 + BP4 → VUS

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 10 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): gnomAD v4.1 total allele frequency 0.000186% (3/1,613,222 alleles) is far below the 0.001% threshold.

gnomad_v4gnomad_v2gnomad_canada

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.043 is well below the 0.249 missense threshold; SpliceAI 0.01 also rules out splice impact.

REVEL score 0.043 (local REVEL v1.3 lookup, chr11:108244963 A>G) - meets VCEP missense BP4 threshold <=0.249SpliceAI max delta score 0.01 (NM_000051.4:c.838A>G) - rules out splice impact (<=0.1); not counted as independent line for missense per lab overrideSun et al. 2025 Table S1 row c.838A>G: REVEL 0.043, AlphaMissense 0.0853, Classification Intermediate, DeepATM_predicted=No - secondary computational corroboration

cspec ↗spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not met: no established pathogenic or likely pathogenic variant producing p.Ile280Val exists; ClinVar lists only uncertain significance for this variant.

PS3 Not assessed: the only functional measurement available (Sun 2025) was equivocal, 'Intermediate', not a confirmed failure to rescue an ATM function.

PS4 Not met: no case-control study of this exact variant exists; the only case-control ATM study in the literature does not list c.838A>G.

PM3 Not assessed: no ataxia-telangiectasia proband observations of this variant (homozygous or in trans) were available.

PP1 Not assessed: no family segregation data for this variant were available (no affected relatives genotyped).

PP3 Not met: REVEL 0.043 is far below the 0.7333 threshold, and SpliceAI 0.01 is far below 0.2.

Benign

BA1 Not met: grpmax filtering allele frequency 0.000553% is roughly 900-fold below the 0.5% threshold.

BS1 Not met: grpmax filtering allele frequency 0.000553% is about 90-fold below the 0.05% threshold.

BS3 Not assessed: the only functional measurement available (Sun 2025) was equivocal, 'Intermediate', not a confirmed rescue of function.

BP2 Not assessed: no unaffected carriers of this variant with a pathogenic ATM variant in trans were documented.

N/A · 16 PVS1 · 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= 1.85963e-06; MAF= 0.00019%, 3/1613222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.333e-05; MAF= 0.00333%, 2/60006 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.99186e-06; MAF= 0.00040%, 1/250510 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.8967e-05; MAF= 0.00290%, 1/34522 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,613,222
0 hom · FAF 0.00055%

Admixed American 2 / 60,006	0.0033%
European (non-Finnish) 1 / 1,179,796	8.5e-05%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 250,510
0 hom

Admixed American

1 / 34,522

0.0029%

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

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories). (ClinVarID = 407462)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.043. BayesDel score = -0.43543.

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.

PMID 40580951

PMID 40580951 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP4 supporting

Corroborates BP4: table REVEL 0.043 matches the primary lookup, AlphaMissense/EVE/boostDM are all low, and the measured Classification is 'Intermediate' (not Non-functional, i.e., no damaging signal)

Rule & framework references · cited for criterion definitions, not variant evidence

32761968 ↗ Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.

34262154 ↗ Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 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

20301317 ↗ Hereditary Ataxia Overview. CLINVAR

20301790 ↗ Ataxia-Telangiectasia. CLINVAR

24418350 ↗ EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

35534704 ↗ The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. CLINVAR

20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR