NM_000051.4:c.5164del

ATM · NP_000042.3:p.(Leu1722TrpfsTer2) · NM_000051.4

GRCh37: chr11:108170598 AC>A · GRCh38: chr11:108299871 AC>A

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.(Leu1722TrpfsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.5164del (p.Leu1722TrpfsTer2) is a frameshift deletion in ATM creating a premature termination codon at amino acid 1723, well upstream of the most C-terminal pathogenic residue p.Arg3047. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay, satisfying PVS1 at Very_Strong strength per the ClinGen HBOP VCEP v1.5.0 ATM PVS1 decision tree.

This variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), meeting the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting.

The variant creates a premature termination codon at codon 1723, upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 criterion for PM5_Supporting, which applies to frameshifting or truncating variants with PTCs upstream of this boundary.

Applying the ClinGen HBOP VCEP v1.5.0 ACMG/AMP combination rules: 1 Very_Strong (PVS1) + 2 Supporting (PM2, PM5) satisfies Rule 4, resulting in a classification of Pathogenic.

Final determination: Rule4 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 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	NM_000051.4:c.5164del is a frameshift deletion resulting in a premature termination codon at p.(Leu1722TrpfsTer2), well upstream of the most C-terminal pathogenic residue p.Arg3047. Under the ATM HBOP VCEP v1.5.0 PVS1 decision tree (adapted from PMID:30192042), this null variant in exon 34 of 63 is predicted to undergo nonsense-mediated decay and meets criteria for PVS1 at Very_Strong strength. Loss of function is an established disease mechanism for ATM in both autosomal recessive ataxia-telangiectasia and autosomal dominant cancer predisposition.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	N/A	PS1 under the ATM HBOP VCEP v1.5.0 applies only to missense variants (with splicing ruled out) or splicing variants evaluated via the ATM PS1 Splicing table. This is a frameshift deletion, not a missense or splicing variant.	cspec
PS2	N/A	PS2 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
PS3	Not assessed	No variant-specific functional evidence was identified for NM_000051.4:c.5164del. Three publications (PMID:27413114, PMID:30348496, PMID:30553448) were reviewed in full text; none mention this variant. Under the ATM VCEP v1.5.0, PS3 requires demonstration that the variant fails to rescue ATM-specific functional features, but no such data are available.
PS4	Not assessed	The ATM VCEP v1.5.0 specifies PS4 requires case-control studies with p<=0.05 and OR>=2 (or lower 95% CI >=1.5). No such study was identified for this variant. The variant is absent from ClinVar and no case-control data are available.	cspec
PS5	N/A	PS5 is a deprecated criterion not included in the ATM HBOP VCEP v1.5.0 specification and is not part of the current ACMG/AMP framework.	cspec
PM1	N/A	PM1 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), satisfying the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting. Absence from large population databases supports pathogenicity.	gnomad_v2 gnomad_v4 cspec
PM4	N/A	The ATM VCEP v1.5.0 restricts PM4 to stop-loss variants. This variant is a frameshift deletion (c.5164del), not a stop-loss variant.	cspec
PM5	Met	Under the ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a PTC at codon 1723, which is well upstream of p.Arg3047 (the most C-terminal pathogenic residue per the VCEP).	cspec vcep_atm_pvs1_1_5
PM6	N/A	PM6 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
PP1	Not assessed	The ATM VCEP v1.5.0 specifies PP1 for autosomal recessive ataxia-telangiectasia segregation (>=1 affected relative for Supporting). No segregation data were identified for this variant. Exploratory evidence retrieval did not return results within the available window.	cspec
PP2	N/A	PP2 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
PP3	N/A	The ATM VCEP v1.5.0 specifies PP3 for missense variants (REVEL >0.7333) or splicing variants (SpliceAI >=0.2). This is a frameshift deletion, not a missense or splicing variant. SpliceAI predicts no significant splice impact (max delta score = 0.02).	cspec spliceai
PP4	N/A	PP4 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
PP5	N/A	PP5 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BA1	Not met	The ATM VCEP v1.5.0 defines BA1 as Grpmax Filtering AF >0.5% in gnomAD v4. This variant is absent from gnomAD v4.1, thus does not satisfy the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	The ATM VCEP v1.5.0 defines BS1 as Grpmax Filtering AF >0.05% in gnomAD v4. This variant is absent from gnomAD v4.1, thus does not satisfy the BS1 threshold.	gnomad_v4 cspec
BS2	N/A	BS2 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BS3	Not assessed	No variant-specific functional evidence demonstrating rescue of ATM-specific features or radiosensitivity was identified for NM_000051.4:c.5164del. Three publications (PMID:27413114, PMID:30348496, PMID:30553448) were reviewed in full text; none mention this variant. Under the ATM VCEP v1.5.0, BS3 requires demonstration that the variant rescues ATM-specific function and/or radiosensitivity.
BS4	N/A	BS4 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BP1	N/A	BP1 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BP2	Not assessed	The ATM VCEP v1.5.0 specifies BP2 for co-occurrence of the variant in trans with a known pathogenic variant in unaffected (non-A-T) individuals, using a point system per the ATM PM3/BP2 table. No co-occurrence data are available for this variant. Exploratory evidence retrieval did not return results within the available window.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BP4	N/A	The ATM VCEP v1.5.0 specifies BP4 for missense variants (REVEL <=0.249) or splicing variants (SpliceAI <=0.1). This is a frameshift deletion, not a missense or splicing variant. While SpliceAI max delta is 0.02 (<=0.1), BP4 is not applied to frameshift variants under the VCEP.	cspec spliceai
BP5	N/A	BP5 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BP6	N/A	BP6 is explicitly marked Not Applicable in the ATM HBOP VCEP v1.5.0 criteria specification.	cspec
BP7	N/A	The ATM VCEP v1.5.0 specifies BP7 for synonymous and deep intronic variants (further than +7 at donor and further than -21 at acceptor sites). This variant is a frameshift coding deletion and does not meet the criteria for BP7.	cspec

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