LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.4:c.5503del
ATM
· NP_000042.3:p.(Thr1835LeufsTer11)
· NM_000051.4
GRCh37: chr11:108175404 GA>G
·
GRCh38: chr11:108304677 GA>G
Gene:
ATM
Transcript:
NM_000051.4
Final call
Pathogenic
PVS1 very strong
PM2 supporting
PM5 supporting
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Thr1835LeufsTer11)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 (Very Strong): frameshift p.(Thr1835LeufsTer11) is predicted to trigger nonsense-mediated decay and removes the critical FAT/PI3K/FATC domain.
2
PM2 (Supporting): absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% threshold, corroborated by gnomAD v2.1 and gnomAD-Canada.
3
PM5 (Supporting): truncating variant with premature stop upstream of the VCEP cutoff residue p.Arg3047.
4
Final classification: Pathogenic, produced by the VCEP combination rule (one very strong plus at least two supporting criteria).
Final determination:
ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985) Rule4: 1 Very Strong (PVS1) plus >=2 Supporting criteria (PM2_Supporting, PM5_Supporting) combines to Pathogenic.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
| Criterion | Status | Rationale | Evidence used |
|---|---|---|---|
| PVS1 | Met | Met at very strong: frameshift p.(Thr1835LeufsTer11) is predicted to trigger nonsense-mediated decay and removes the critical FAT/PI3K/FATC domain. |
cspec
vcep_atm_pvs1_1_5
pvs1_gene_context
pvs1_variant_assessment
pvs1_generic_framework
gnomad_v2
gnomad_v4
|
| PS1 | N/A | Not applicable: PS1 applies only to missense changes, and this variant is a frameshift. |
cspec
spliceai
|
| PS2 | N/A | Not applicable: the ATM VCEP forbids de novo criteria for this gene, and no de novo occurrence was reported. |
cspec
|
| PS3 | Not assessed | Not assessed: no validated functional assay result for this variant was available. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
vcep_suppl_tables1_pmid_40580951
|
| PS4 | Not assessed | Not assessed: no case-control enrichment data for this variant was available. |
cspec
PMID:25394175
|
| PM1 | N/A | Not applicable: the ATM VCEP marks PM1 unused, and this is a frameshift rather than a missense variant. |
cspec
|
| PM2 | Met | Met at supporting: absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no affected-proband genotype, in-trans second allele, or phase evidence was available. |
cspec
vcep_atm_pm3_bp2_1_5
|
| PM4 | N/A | Not applicable: PM4 is reserved for stop-loss variants; this frameshift creates a premature stop, already captured by PVS1. |
cspec
|
| PM5 | Met | Met at supporting: truncating variant with premature stop upstream of the VCEP cutoff residue p.Arg3047. |
cspec
pm5_candidates
|
| PM6 | N/A | Not applicable: the ATM VCEP forbids assumed-de-novo criteria, and none was reported. |
cspec
|
| PP1 | Not assessed | Not assessed: no segregation data in affected relatives was available for this variant. |
cspec
|
| PP2 | N/A | Not applicable: PP2 is a missense-oriented criterion and does not apply to a truncating variant. |
cspec
|
| PP3 | N/A | Not applicable: PP3 applies to missense or splice-relevant variants, not to this coding frameshift. |
cspec
spliceai
|
| PP4 | N/A | Not applicable: the ATM VCEP marks PP4 as unused. |
cspec
|
| PP5 | Not assessed | Not assessed: no expert-panel ClinVar assertion exists; the single laboratory submission is not expert-panel evidence. |
clinvar
|
| BA1 | Not met | Not met: absent from gnomAD v4.1 (AF=0), below the >0.5% BA1 population-frequency threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS1 | Not met | Not met: absent from gnomAD v4.1 (AF=0), below the >0.05% BS1 population-frequency threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS2 | N/A | Not applicable: the ATM VCEP marks BS2 as unused for ATM. |
cspec
|
| BS3 | Not assessed | Not assessed: no validated functional evidence of normal protein function was available. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
vcep_suppl_tables1_pmid_40580951
|
| BS4 | N/A | Not applicable: the ATM VCEP forbids lack-of-co-segregation evidence for this gene. |
cspec
|
| BP1 | N/A | Not applicable: BP1 targets missense variants, not premature truncating changes. |
cspec
|
| BP2 | Not assessed | Not assessed: no unaffected-carrier co-occurrence, phase, or homozygosity evidence was available. |
cspec
vcep_atm_pm3_bp2_1_5
|
| BP3 | N/A | Not applicable: BP3 targets in-frame indels in nonfunctional repeats; this is a frameshift in a constitutive exon. |
cspec
|
| BP4 | N/A | Not applicable: BP4 targets missense or synonymous/intronic variants; this is a coding frameshift. |
cspec
spliceai
|
| BP5 | N/A | Not applicable: the ATM VCEP marks BP5 as unused. |
cspec
|
| BP6 | Not assessed | Not assessed: no expert-panel benign ClinVar assertion exists for this variant. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 targets synonymous or deep-intronic variants; this is a coding frameshift. |
cspec
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.