Starting

Initialising…

ATM

Final classification

Likely Pathogenic

ATM c.3137T>C · p.Leu1046Pro

ATM

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

Gene

ATM

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.3137T>C

Consequence

N/A

GRCh38

chr11:108272591 T>C

GRCh37

chr11:108143318 T>C

Basis ATM HBOP CSPEC/VCEP v1.5.0 cspec_ruleset final-classification framework from final_classification_framework.json; Rule19 applies. ▾

ATM HBOP CSPEC/VCEP v1.5.0 cspec_ruleset final-classification framework from final_classification_framework.json; Rule19 applies.

Classification rationale

PP3 Likely Pathogenic

ATM c.3137T>C

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles; 0 homozygotes), with the highest observed frequency in the South Asian population at 2.19587e-05 (2/91080 alleles; 0 homozygotes).² In silico evidence supports a deleterious missense effect, with REVEL 0.854 exceeding the ATM PP3 threshold of 0.7333, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).³

PP3 → Likely Pathogenic

1 evidence.json:cosmicevidence.json:clinvar

2 evidence.json:gnomad

3 prefetch.json:revelevidence.json:spliceaicase_summary.json:cspec

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85893e-06; MAF= 0.00019%, 3/1613832 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19587e-05; MAF= 0.00220%, 2/91080 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,613,832
0 hom · FAF 0.00037%

South Asian 2 / 91,080	0.0022%
European (non-Finnish) 1 / 1,179,776	8.5e-05%

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

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots