Variant classification summary

NM_000051.3:c.5515C>T

ATM · NP_000042.3:p.(Gln1839Ter) · NM_000051.3

GRCh37: chr11:108175420 C>T · GRCh38: chr11:108304693 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.(Gln1839Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.5515C>T (p.Gln1839Ter; p.Q1839*) variant has been reported in ClinVar as pathogenic, including expert panel review.

2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 0.00087% (14/1613854 alleles) with no homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%.

3

This nonsense variant introduces a premature stop codon at residue 1839, and the ATM VCEP PVS1 framework supports loss of function as a disease mechanism for ATM.

4

SpliceAI predicts no strong splice effect for this variant (max delta score 0.16), which is below the ATM PP3 splicing threshold of 0.2 and above the BP4 threshold of 0.1, so computational evidence does not independently change the interpretation.

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 nonsense variant introduces a premature termination codon at p.Gln1839Ter (p.Q1839*), well upstream of the 3' end of ATM, and ATM loss of function is an established disease mechanism in the applicable ATM VCEP framework. The ATM PVS1 guidance supports full-strength PVS1 for a truncating variant of this type.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	ATM PS1 guidance is written for missense changes producing the same amino acid substitution or for splice variants with the same predicted or observed splice event. This variant is a nonsense substitution, so PS1 does not apply.	cspec vcep_atm_ps1_1_5
PS2	N/A	PS2 is marked not applicable in the ATM VCEP specification, so de novo evidence is not used under this framework.	cspec
PS3	Not assessed	Published studies reviewed describe ATM loss of function and radiosensitivity in affected cells more broadly, but no validated variant-specific rescue assay was identified for this variant. The ATM VCEP also notes that phenotypic evidence such as deficient ATM activity in patient cells should not be used alone as functional evidence for PS3.	cspec PMID:10873394 PMID:22213089
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study, odds ratio, or exact-variant enrichment statistic meeting the ATM PS4 requirement was identified. Available evidence does not establish PS4 at this time.	cspec clinvar
PM1	N/A	PM1 is marked not applicable in the ATM VCEP specification, so hotspot or critical-domain localization is not used as PM1 evidence in this framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an overall allele frequency of 8.674886328007367e-06 (0.00087%; 14/1613854 alleles) with 0 homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%. This supports PM2 at supporting strength.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No confirmed observations of this variant in trans with a pathogenic ATM variant in an affected individual were identified, so PM3 cannot be assigned from the available evidence.	vcep_atm_pm3_bp2_1_5 clinvar
PM4	N/A	ATM PM4 is specified for stop-loss variants. This variant is a nonsense change, so PM4 does not apply.	cspec
PM5	Met	The ATM VCEP specifies PM5_Supporting for truncating variants with a premature termination codon upstream of p.Arg3047. This variant creates p.Gln1839Ter, which is upstream of p.Arg3047, so PM5 is met at supporting strength.	cspec
PM6	N/A	PM6 is marked not applicable in the ATM VCEP specification, so assumed de novo evidence is not used under this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assigned. The available evidence does not show segregation with an ATM-related recessive phenotype in informative relatives.	cspec clinvar
PP2	N/A	PP2 is marked not applicable in the ATM VCEP specification.	cspec
PP3	Not met	SpliceAI predicts a maximum delta score of 0.16, which is below the ATM PP3 splicing threshold of 0.2. REVEL is not available because this is not a missense variant, and the available BayesDel score does not substitute for the ATM VCEP PP3 rule. PP3 is therefore not met.	spliceai bayesdel cspec
PP4	N/A	PP4 is marked not applicable in the ATM VCEP specification.	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	The gnomAD v4.1 frequency for this variant is 0.00087%, which is far below the ATM BA1 threshold of greater than 0.5%. BA1 is not met.	gnomad_v4 cspec
BS1	Not met	The highest observed frequency remains well below the ATM BS1 threshold of greater than 0.05% in gnomAD v4. Available population data do not support BS1.	gnomad_v4 cspec
BS2	N/A	BS2 is marked not applicable in the ATM VCEP specification.	cspec
BS3	Not assessed	No variant-specific assay showing rescue of ATM-specific function or radiosensitivity was identified. Available evidence does not support BS3 for this variant.	cspec PMID:10873394 PMID:22213089
BS4	N/A	BS4 is marked not applicable in the ATM VCEP specification.	cspec
BP1	N/A	BP1 is marked not applicable in the ATM VCEP specification.	cspec
BP2	Not assessed	No confirmed co-occurrence of this variant in trans with a pathogenic ATM variant in an unaffected individual was identified, so BP2 cannot be assigned from the available evidence.	vcep_atm_pm3_bp2_1_5 clinvar
BP3	N/A	BP3 is marked not applicable in the ATM VCEP specification.	cspec
BP4	Not met	SpliceAI predicts a maximum delta score of 0.16, which is above the ATM BP4 no-splice-impact threshold of 0.1. The missense-based REVEL rule is not applicable to this nonsense variant. BP4 is therefore not met.	spliceai cspec
BP5	N/A	BP5 is marked not applicable in the ATM VCEP specification.	cspec
BP6	N/A	BP6 is marked not applicable in the ATM VCEP specification.	cspec
BP7	N/A	BP7 is specified for synonymous and deep intronic variants. This variant is a nonsense coding change, so BP7 does not apply.	cspec

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