The ATM c.2413C>T (p.Arg805Ter; p.R805*) variant has been reported in ClinVar as Pathogenic by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel and is also cataloged in a cancer knowledgebase with variant-specific somatic context.1 This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00081% (13/1613688) with a highest observed East Asian frequency of 0.00669% (3/44820); these values are below the ATM BS1 and BA1 thresholds but the East Asian frequency is above the ATM PM2_Supporting threshold of 0.001%.2 Curated literature resources identify this variant in an ATM loss-of-function context, but no ATM-specific functional rescue data were confirmed here that meet the expert-panel requirements for PS3 or BS3.3 This variant introduces a premature termination codon at Arg805, well upstream of the ATM truncation cutoff used by the expert panel, which supports PVS1 and PM5_Supporting under the ATM-specific rules; REVEL was unavailable, BayesDel was 0.588046, and no SpliceAI-based evidence was captured for a splice-specific computational call.4
ATM
Final classification
Pathogenic
ATM c.2413C>T · p.Arg805Ter
ATM
The ATM c.2413C>T (p.Arg805Ter; p.R805*) variant has been reported in ClinVar as Pathogenic by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel and is also cataloged in a cancer knowledgebase with variant-specific somatic context.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM5 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM5PP5
Pathogenic
ATM c.2413C>T
PVS1 + PM5 + PP5
→
Pathogenic
4
cspec ↗vcep_atm_pvs1_1_5pvs1_variant_assessmentbayesdelspliceai ↗
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
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= 8.05608e-06; MAF= 0.00081%, 13/1613688 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.69344e-05; MAF= 0.00669%, 3/44820 alleles, homozygotes = 0); grpmax FAF= 1.775e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98067e-05; MAF= 0.00398%, 10/251214 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0003263; MAF= 0.03263%, 6/18388 alleles, homozygotes = 0); grpmax FAF= 0.00014149.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00081%
· 13 / 1,613,688
0 hom · FAF 0.0018%
0 hom · FAF 0.0018%
East Asian 3 / 44,820 |
0.0067% |
South Asian 3 / 91,072 |
0.0033% |
Remaining individuals 1 / 62,490 |
0.0016% |
European (Finnish) 1 / 63,850 |
0.0016% |
European (non-Finnish) 5 / 1,179,898 |
0.00042% |
+ 5 not observed (Admixed American, Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.004%
· 10 / 251,214
0 hom · FAF 0.014%
0 hom · FAF 0.014%
East Asian 6 / 18,388 |
0.033% |
South Asian 2 / 30,598 |
0.0065% |
European (non-Finnish) 2 / 113,634 |
0.0018% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 216021)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18). BayesDel score = 0.588046.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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; COSV53736642, n = 11 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
30348496 ↗
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
ONCOKB
30553448 ↗
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
ONCOKB
12815592 ↗
Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.
CLINVAR
15843990 ↗
ATM haplotypes and associated mutations in Iranian patients with ataxia-telangiectasia: recurring homozygosity without a founder haplotype.
CLINVAR
16941484 ↗
ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions.
CLINVAR
17910737 ↗
Large genomic mutations within the ATM gene detected by MLPA, including a duplication of 41 kb from exon 4 to 20.
CLINVAR
19691550 ↗
Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR