The ATM c.7517_7520del (p.Arg2506ThrfsTer3) variant has been reported in ClinVar as pathogenic and is cataloged by OncoKB as a likely oncogenic loss-of-function alteration.1 This variant is rare in population databases, with an overall allele frequency of 5.58e-06 (9/1,612,790 alleles) in gnomAD v4.1 and 7.99e-06 (2/250,380 alleles) in gnomAD v2.1, supporting rarity.2 No variant-specific functional rescue or loss-of-function assay meeting the ATM VCEP PS3 or BS3 requirements was identified.3 This frameshift variant is predicted to truncate ATM at p.Arg2508, and the ATM VCEP framework supports PVS1 for qualifying truncating variants; the ATM CSPEC also allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Arg3047.4
ATM
Final classification
Pathogenic
ATM c.7517_7520del · p.Arg2506ThrfsTer3
ATM
The ATM c.7517_7520del (p.Arg2506ThrfsTer3) variant has been reported in ClinVar as pathogenic and is cataloged by OncoKB as a likely oncogenic loss-of-function alteration.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework; Rule4 applies.
Classification rationale
PVS1PM2PM5
Pathogenic
ATM c.7517_7520del
PVS1 + PM2 + PM5
→
Pathogenic
4
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_a_t_m___p_v_s_1___1___5
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.58039e-06; MAF= 0.00056%, 9/1612790 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19877e-05; MAF= 0.00220%, 2/90960 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.98786e-06; MAF= 0.00080%, 2/250380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27955e-05; MAF= 0.00328%, 1/30492 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,612,790
0 hom · FAF 0.00037%
0 hom · FAF 0.00037%
South Asian 2 / 90,960 |
0.0022% |
European (non-Finnish) 7 / 1,179,424 |
0.00059% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 250,380
0 hom
0 hom
South Asian 1 / 30,492 |
0.0033% |
European (non-Finnish) 1 / 113,310 |
0.00088% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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; COSV108796282, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links