NM_000051.4:c.9041_9042del

ATM · NP_000042.3:p.(Gln3014ArgfsTer48) · NM_000051.4

GRCh37: chr11:108236104 CAA>C · GRCh38: chr11:108365377 CAA>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Gln3014ArgfsTer48)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 is met at Very Strong strength: NM_000051.4:c.9041_9042del is a frameshift deletion resulting in a premature termination codon (p.Gln3014ArgfsTer48) upstream of the p.Arg3047 threshold in a gene where loss of function is an established disease mechanism. The PTC is NMD-competent per the ClinGen SVI PVS1 framework and the ATM VCEP PVS1 decision tree.

PM2 is met at Supporting strength: this variant is absent from gnomAD v4.1 (allele count 0), meeting the ATM VCEP threshold of ≤0.001% allele frequency in gnomAD v4.

No benign or conflicting evidence was identified: BA1 and BS1 are not met (variant absent from gnomAD); PS3/BS3 functional evidence was sought but no variant-specific functional data were found in the reviewed literature or VCEP reference tables.

Under the ATM VCEP v1.5.0 final combination rules, Rule 19 is triggered: 1 Very Strong pathogenic criterion (PVS1) + 1 Supporting pathogenic criterion (PM2_Supporting) yields a classification of Likely Pathogenic.

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely 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	This frameshift deletion (c.9041_9042del) introduces a premature termination codon at p.Gln3014ArgfsTer48 in exon 63 of ATM. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay (PTC is not in the last exon and is >55 nt upstream of the final exon-exon junction). The truncation occurs upstream of the p.Arg3047 critical C-terminal threshold defined by the ATM VCEP v1.5.0 PVS1 decision tree, supporting PVS1 at Very Strong strength.	cspec pvs1_generic_framework vcep_atm_pvs1_1_5
PS1	N/A	ATM VCEP PS1 rules apply only to missense or splicing variants at the same nucleotide/residue. This variant is a frameshift deletion.	vcep_atm_ps1_1_5
PS2	N/A	PS2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
PS3	Not assessed	No variant-specific functional evidence was identified for NM_000051.4:c.9041_9042del. Three PMIDs (27413114, 30348496, 30553448) were reviewed in full text; all discuss ATM function at the gene level but none studies this specific variant. ATM VCEP functional assay reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) list approved PS3/BS3 assay frameworks but do not include data for this variant. Suppl_TableS1 (PMID:40580951) contains only SNV functional scores and does not include this deletion.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	No case-control studies or systematic case observation data were identified for this specific variant. An exploratory literature search found no curated case counts comparing prevalence in affected individuals versus controls. The variant is absent from gnomAD, which is consistent with rarity but does not independently satisfy PS4 without case data.
PS5	N/A	The ATM VCEP does not define PS5 criteria. The supporting counterpart (PP5) is explicitly marked Not Applicable by the VCEP, consistent with the framework's approach of not assigning weight to ClinVar classifications without accessible primary evidence.	cspec
PM1	N/A	PM1 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 (allele count 0). Per ATM VCEP v1.5.0, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. The variant is also absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 cspec
PM4	N/A	Per ATM VCEP v1.5.0, PM4 is restricted to stop-loss variants. This variant is a frameshift deletion, not a stop-loss variant.	cspec
PM5	Not met	The ATM VCEP PM5 rule states: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.' The premature termination codon created by this variant is at position 3061 (p.Gln3014ArgfsTer48), which is downstream of the p.Arg3047 threshold. Per strict reading of the VCEP rule, the PTC position rather than the variant start position determines eligibility; therefore PM5 does not apply.	cspec
PM6	N/A	PM6 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
PP1	Not assessed	No cosegregation data were identified for this variant. Per ATM VCEP, PP1 for the recessive A-T condition requires segregation in affected relatives (1/2/3+ affected relatives for Supporting/Moderate/Strong). No family studies reporting this variant were found.	cspec
PP2	N/A	PP2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
PP3	N/A	Per ATM VCEP v1.5.0, PP3 applies to missense variants (REVEL >0.7333) or splicing variants (SpliceAI ≥0.2). This is a frameshift deletion; REVEL and BayesDel scores are not applicable, and SpliceAI returned no delta scores for this variant. In silico prediction tools are not designed to assess the functional impact of frameshift variants.	cspec spliceai
PP4	N/A	PP4 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
PP5	N/A	PP5 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BA1	Not met	Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4. The variant is absent from gnomAD v4.1 (allele count 0), which is far below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4. The variant is absent from gnomAD v4.1 (allele count 0), which is far below the BS1 threshold.	gnomad_v4 cspec
BS2	N/A	BS2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BS3	Not assessed	No variant-specific functional evidence demonstrating rescue of ATM function was identified. Three PMIDs (27413114, 30348496, 30553448) were reviewed in full text; all discuss ATM generally but none studies this specific variant. Per ATM VCEP, BS3 requires evidence that the variant rescues ATM-specific features and/or radiosensitivity. No such data are available for this variant.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	BS4 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BP1	N/A	BP1 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BP2	Not assessed	No data were identified regarding observation of this variant in cis or trans with other pathogenic ATM variants. BP2 requires points from the ATM PM3/BP2 table based on observations in unaffected individuals. No such observations are available for this variant.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BP4	N/A	Per ATM VCEP v1.5.0, BP4 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). This is a frameshift deletion; in silico missense and splicing predictors are not applicable to this variant class.	cspec
BP5	N/A	BP5 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BP6	N/A	BP6 is explicitly marked Not Applicable by the ATM VCEP v1.5.0.	cspec
BP7	N/A	Per ATM VCEP v1.5.0, BP7 applies to synonymous and deep intronic variants. This is a frameshift deletion.	cspec

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