LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.4:c.7628dupA
ATM
· NP_000042.3:p.(Asn2543LysfsTer5)
· NM_000051.4
GRCh37: chr11:108202281 T>TA
·
GRCh38: chr11:108331554 T>TA
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.(Asn2543LysfsTer5)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 (Very Strong): one-base frameshift p.(Asn2543LysfsTer5) predicted to trigger nonsense-mediated decay, truncating about 510 residues.
2
PM2 (Supporting): absent from gnomAD v4.1, below the <=0.001% population frequency threshold.
3
PM5 (Supporting): premature termination upstream of the p.Arg3047 ATM truncation cutoff.
4
Pathogenic: ATM VCEP v1.5 Rule4, combining 1 very strong and 2 supporting criteria.
Final determination:
Rule4 of the ATM VCEP v1.5 criteria-combination framework classifies one Pathogenic Very Strong criterion plus at least two Pathogenic Supporting criteria as 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: one-base frameshift creates premature stop codon p.(Asn2543LysfsTer5) predicted to trigger nonsense-mediated decay, truncating about 510 residues. |
cspec
vcep_atm_pvs1_1_5
|
| PS1 | N/A | Not applicable: PS1 applies only to missense or splice-region variants; this is a frameshift. |
cspec
vcep_atm_ps1_1_5
|
| PS2 | N/A | Not applicable: the ATM VCEP excludes de novo PS2 for autosomal dominant/recessive disease, and no parental testing was available. |
cspec
|
| PS3 | Not assessed | Not assessed: no variant-specific validated functional assay result was available. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
|
| PS4 | Not assessed | Not assessed: no case-control study met the required threshold (p-value <=0.05 and odds/hazard/relative risk >=2). |
cspec
|
| PM1 | N/A | Not applicable: the ATM VCEP marks PM1 as not applicable, and this is a frameshift, not a missense variant. |
cspec
|
| PM2 | Met | Met (supporting): absent from gnomAD v4.1, below the <=0.001% frequency threshold. |
cspec
gnomad_v4
gnomad_v2
gnomad_canada
|
| PM3 | Not assessed | Not assessed: no affected proband, second variant, or trans-phase observation was available to assign points. |
vcep_atm_pm3_bp2_1_5
clinvar
|
| PM4 | N/A | Not applicable: PM4 is restricted to stop-loss variants; this frameshift creates a premature stop codon. |
cspec
|
| PM5 | Met | Met (supporting): the premature stop at approximately p.2547 lies upstream of the p.Arg3047 ATM truncation cutoff. |
cspec
pm5_candidates
|
| PM6 | N/A | Not applicable: the ATM VCEP excludes assumed de novo status without confirmed parentage, and none was documented. |
cspec
|
| PP1 | Not assessed | Not assessed: no affected relatives, pedigree genotypes, or phase information was available for segregation analysis. |
cspec
PMID:25614872
|
| PP2 | N/A | Not applicable: the ATM VCEP designates PP2 as not applicable. |
cspec
|
| PP3 | N/A | Not applicable: PP3 covers missense or splice-primary variants; this exonic frameshift is outside those sub-paths (SpliceAI max delta 0.028). |
cspec
spliceai
|
| PP4 | N/A | Not applicable: the ATM VCEP designates PP4 as not applicable. |
cspec
|
| PP5 | N/A | Not applicable: the ATM VCEP designates PP5 as not applicable, and ClinVar has no expert-panel submission. |
cspec
clinvar
|
| BA1 | Not met | Not met: absent from gnomAD v4.1, far below the >0.5% filtering allele frequency threshold. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: absent from gnomAD v4.1, below the >0.05% disease-compatible frequency threshold. |
cspec
gnomad_v4
|
| BS2 | N/A | Not applicable: the ATM VCEP designates BS2 as not applicable. |
cspec
|
| BS3 | Not assessed | Not assessed: no variant-specific functional assay demonstrating normal ATM function was available. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
|
| BS4 | N/A | Not applicable: the ATM VCEP designates BS4 as not applicable. |
cspec
|
| BP1 | N/A | Not applicable: the ATM VCEP designates BP1 as not applicable. |
cspec
|
| BP2 | Not assessed | Not assessed: no unaffected co-occurrence, second variant, or phase information was available. |
vcep_atm_pm3_bp2_1_5
clinvar
|
| BP3 | N/A | Not applicable: BP3 is excluded by the ATM VCEP, and this frameshift duplication is not in-frame. |
cspec
|
| BP4 | N/A | Not applicable: BP4 sub-paths cover missense or splice-primary variants; this exonic frameshift is neither. |
cspec
spliceai
|
| BP5 | N/A | Not applicable: the ATM VCEP designates BP5 as not applicable. |
cspec
|
| BP6 | N/A | Not applicable: the ATM VCEP designates BP6 as not applicable, and ClinVar has no expert-panel benign assertion. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: BP7 applies to synonymous or deep intronic variants; this is an exonic 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.