Variant classification summary

NM_000051.3:c.67C>T

ATM · NP_000042.3:p.(Arg23Ter) · NM_000051.3

GRCh37: chr11:108098418 C>T · GRCh38: chr11:108227691 C>T

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Arg23Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.67C>T (p.Arg23Ter, p.R23*) variant is reported in ClinVar as pathogenic, including a pathogenic expert panel classification, and it also has variant-specific cancer curation in OncoKB.

2

This variant is rare in population databases, with gnomAD v4.1 AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles; no homozygotes), which is below the ATM PM2 threshold of 0.001%.

3

In an ATM supplementary SNV table, this variant was categorized as non-functional with medium-high confidence, which is consistent with a damaging loss-of-function effect, although the available summary alone does not establish ATM VCEP PS3 weighting.

4

This is a nonsense variant predicted to create a very early stop codon; SpliceAI predicts no significant splice impact with a max delta score of 0.00, and the ATM computational PP3/BP4 rules are not used here because they are defined for missense or specified splicing contexts rather than truncating variants.

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	This variant is a nonsense change, NM_000051.3:c.67C>T (p.Arg23Ter, p.R23*), that introduces a very early premature stop codon in ATM. The ATM VCEP includes PVS1 guidance, loss of function is an established disease mechanism for ATM, and this early truncating event is consistent with full-strength PVS1 under the ATM PVS1 decision framework.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Available evidence does not support PS1 because this variant is a nonsense change, and the ATM PS1 specification is directed to missense or defined splicing equivalence scenarios rather than truncating variants such as p.(Arg23Ter).	cspec vcep_atm_ps1_1_5
PS2	N/A	The ATM VCEP marks PS2 as not applicable in this framework.	cspec
PS3	Not assessed	Variant-specific functional literature and an ATM supplementary SNV table were identified, and the supplementary table categorized this variant as non-functional with medium-high confidence. However, the available summary does not establish the ATM VCEP-required rescue assay result needed to assign PS3 strength.	oncokb vcep_suppl_tables1_pmid_40580951 cspec
PS4	Not assessed	This variant has been reported in ClinVar and in published literature, but no case-control study or exact affected-versus-control enrichment meeting the ATM VCEP PS4 threshold was identified. Available evidence is therefore insufficient to assign PS4.	clinvar cspec PMID:23807571 PMID:25614872 PMID:26896183 PMID:29753700
PM1	N/A	The ATM VCEP marks PM1 as not applicable in this framework.	cspec
PM2	Met	This variant is present in gnomAD v4.1 at AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles) with no homozygotes, which is below the ATM PM2 threshold of 0.001%. This rarity supports PM2 at supporting strength.	gnomad_v4 cspec
PM3	Not assessed	No confirmed trans observations, homozygous affected observations, or other point-scored evidence meeting the ATM PM3 framework were identified for this variant.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Available evidence does not support PM4 because the ATM VCEP uses PM4 for stop-loss variants, and this variant is a nonsense change.	cspec
PM5	Met	This variant is a truncating variant with a premature termination codon at p.Arg23, which is far upstream of the ATM PM5 cutoff at p.Arg3047. This meets the ATM-specific PM5 supporting rule for truncating variants.	cspec
PM6	N/A	The ATM VCEP marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No segregation data were identified to show this variant tracking with disease in affected relatives under the ATM PP1 framework.	cspec PMID:23807571 PMID:25614872 PMID:26896183 PMID:29753700
PP2	N/A	The ATM VCEP marks PP2 as not applicable in this framework.	cspec
PP3	N/A	Available computational evidence was reviewed, including SpliceAI and BayesDel, but the ATM PP3 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00.	cspec spliceai bayesdel
PP4	N/A	The ATM VCEP marks PP4 as not applicable in this framework.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BA1 threshold of greater than 0.5%.	gnomad_v4 cspec
BS1	Not met	This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BS1 threshold of greater than 0.05%.	gnomad_v4 cspec
BS2	N/A	The ATM VCEP marks BS2 as not applicable in this framework.	cspec
BS3	Not met	Available evidence does not support BS3. The ATM VCEP requires rescue of an ATM-specific feature and/or radiosensitivity for benign functional evidence, and the available supplementary summary instead categorized this variant as non-functional.	cspec vcep_suppl_tables1_pmid_40580951
BS4	N/A	The ATM VCEP marks BS4 as not applicable in this framework.	cspec
BP1	N/A	The ATM VCEP marks BP1 as not applicable in this framework.	cspec
BP2	Not assessed	No unaffected in-trans observations, phase-unknown benign point-scored observations, or homozygous unaffected observations meeting the ATM BP2 framework were identified for this variant.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM VCEP marks BP3 as not applicable in this framework.	cspec
BP4	N/A	Available computational evidence was reviewed, but the ATM BP4 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00.	cspec spliceai bayesdel
BP5	N/A	The ATM VCEP marks BP5 as not applicable in this framework.	cspec
BP6	N/A	The ATM VCEP marks BP6 as not applicable in this framework.	cspec
BP7	N/A	Available evidence does not support BP7 because this variant is a nonsense coding change rather than a synonymous or qualifying deep intronic variant.	cspec

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