Classification rationale

BA1BS1BP4BP6 Benign

ATM c.3118A>G

The ATM c.3118A>G (p.Met1040Val) variant has been observed in somatic cancers 4 times in COSMIC and is reported in ClinVar as Benign with expert panel review.¹ This variant is common in population databases, with gnomAD v4.1 showing an overall allele frequency of 0.20969% and an African/African American allele frequency of 3.97073%, which exceeds the ATM BA1 threshold of 0.5% grpmax filtering allele frequency.² Computational evidence supports a benign effect, with REVEL 0.096, BayesDel -0.451498, and SpliceAI maximum delta score 0.01, meeting the ATM BP4 thresholds and not meeting PP3 thresholds.³

BA1 + BS1 + BP4 + BP6 → Benign

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_000051.3 · variants mapped to exon structure

ATM NM_000051.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 9 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant exceeds the ATM BA1 threshold of >0.5% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, with grpmax FAF 3.85176%.

ATM BA1 threshold: grpmax filtering AF >0.5% in gnomAD v4gnomAD v4.1 African/African American AF 0.0397073grpmax FAF 0.0385176

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BS1 strong Benign

This variant exceeds the ATM BS1 threshold of >0.05% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, which is far above this threshold.

ATM BS1 threshold: grpmax filtering AF >0.05% in gnomAD v4gnomAD v4.1 African/African American AF 0.0397073gnomAD v2.1 African/African American AF 0.0418838

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

BP4 supporting Benign

Computational evidence supports a benign effect. REVEL is 0.096, below the ATM BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the BP4 splice threshold of ≤0.1. BayesDel is also negative at -0.451498, which is concordant with a benign computational profile.

REVEL 0.096SpliceAI max delta score 0.01BayesDel -0.451498

cspec ↗spliceai ↗

BP6 supporting Benign

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.

ATM CSPEC applicability: BP6 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 6 not assessed

Pathogenic

PS1 No established pathogenic or likely pathogenic comparator producing the same amino acid change or the same predicted splice event was identified, so PS1 was not assessed.

PS3 No validated ATM functional study for this exact variant was identified showing failure to rescue an ATM-specific feature or radiosensitivity in a manner that meets the ATM PS3 framework.

PS4 This variant has been reported in ClinVar and 4 times in COSMIC, but no case-control study showing p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥2 was identified.

PM2 Population frequency is above the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4.1.

PM3 No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia was identified.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP3 Computational evidence does not meet the ATM PP3 threshold.

Benign

BS3 No validated ATM functional study for this exact variant was identified showing rescue of an ATM-specific feature and/or radiosensitivity in a manner that meets the ATM BS3 framework.

BP2 No confirmed cis or trans co-occurrence data with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual were identified, so BP2 was not assessed.

N/A · 15 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00209693; MAF= 0.20969%, 3384/1613784 alleles, homozygotes = 67) and has highest observed frequency in the African/African American population (AF= 0.0397073; MAF= 3.97073%, 2979/75024 alleles, homozygotes = 67); grpmax FAF= 0.0385176.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00399369; MAF= 0.39937%, 1129/282696 alleles, homozygotes = 26) and has highest observed frequency in the African/African American population (AF= 0.0418838; MAF= 4.18838%, 1045/24950 alleles, homozygotes = 26); grpmax FAF= 0.0399312.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.21% · 3384 / 1,613,784
67 hom · FAF 3.9%

African/African American 2979 / 75,024	4% 67 hom
Remaining individuals 190 / 62,490	0.3%
Admixed American 162 / 60,024	0.27%
Middle Eastern 9 / 6,056	0.15%
South Asian 15 / 91,076	0.016%
European (non-Finnish) 29 / 1,179,760	0.0025%

+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.4% · 1129 / 282,696
26 hom · FAF 4%

African/African American 1045 / 24,950	4.2% 26 hom
Admixed American 62 / 35,420	0.18%
Remaining individuals 11 / 7,212	0.15%
South Asian 3 / 30,608	0.0098%
European (non-Finnish) 8 / 129,074	0.0062%

+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (22 clinical laboratories) and as Likely benign (5 clinical laboratories) and as benign (1 clinical laboratory) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3027)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.096. BayesDel score = -0.451498.

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; COSV53737085, n = 4 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 · 9 PMIDs not cited in assessment

11443540 ↗ Global analysis of ATM polymorphism reveals significant functional constraint. CLINVAR

17640065 ↗ A systematic evaluation of the ataxia telangiectasia mutated gene does not show an association with non-Hodgkin lymphoma. CLINVAR

20305132 ↗ Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. CLINVAR

22529920 ↗ Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. CLINVAR

25625042 ↗ ATM gene mutations in sporadic breast cancer patients from Brazil. CLINVAR

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

9288106 ↗ Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. CLINVAR

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

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