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 ↗

Gene diagram · NM_000051.3 · variants mapped to exon structure

ATM NM_000051.3

Fetching transcript structure from UCSC…

Applied criteria · 4 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 · 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