Variant classification summary

NM_000051.4:c.419A>T

ATM · NP_000042.3:p.(Asp140Val) · NM_000051.4

GRCh37: chr11:108106484 A>T · GRCh38: chr11:108235757 A>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asp140Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.419A>T (p.(Asp140Val), p.(D140V)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%.

3

In an ATM supplementary functional dataset, p.(D140V) was classified as Functional with High confidence, but the available retrieved evidence does not provide the assay-level rescue details required to assign ATM PS3 or BS3 in this pass.

4

Computational evidence supports a damaging missense effect: REVEL is 0.815, above the ATM PP3 threshold of greater than 0.7333, BayesDel is 0.278827, and SpliceAI shows no significant splice impact with a maximum delta score of 0.06.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	N/A	This is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant. ATM loss of function is an established disease mechanism, but this variant does not meet the ATM PVS1 decision-tree entry criteria.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not assessed	No pathogenic or likely pathogenic comparator causing the same amino acid change or the same defined splice event was identified from the available ATM-specific materials, so PS1 was not established.	cspec vcep_atm_ps1_1_5
PS2	N/A	The ATM VCEP framework marks PS2 as not applicable for this gene-specific specification.	cspec
PS3	Not assessed	An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not provide assay-level rescue results for ATM-specific function and radiosensitivity needed to apply ATM PS3.	cspec vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	No case-control data or enrichment data meeting the ATM PS4 rule were identified. This variant is also absent from ClinVar, so there is no assembled case series evidence to support PS4 in this pass.	cspec clinvar
PM1	N/A	The ATM VCEP framework marks PM1 as not applicable.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. A frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%, so PM2_Supporting is met.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No proband data showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 points cannot be assigned.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	ATM PM4 is specified for stop-loss variants, and this variant is a missense substitution.	cspec
PM5	N/A	In the ATM VCEP framework, PM5 is a truncation-cutoff or related non-missense rule rather than classic same-residue missense PM5. This missense variant is therefore not eligible for PM5 under the governing rule set.	cspec pm5_candidates
PM6	N/A	The ATM VCEP framework marks PM6 as not applicable.	cspec
PP1	Not assessed	No family segregation data were identified, so PP1 cannot be applied.	cspec
PP2	N/A	The ATM VCEP framework marks PP2 as not applicable.	cspec
PP3	Met	This missense variant has a REVEL score of 0.815, which is above the ATM PP3 threshold of greater than 0.7333. SpliceAI shows a maximum delta score of 0.06, which does not suggest a splice effect, so the computational evidence supports a damaging missense effect and PP3 is met at supporting strength.	cspec revel spliceai bayesdel
PP4	N/A	The ATM VCEP framework marks PP4 as not applicable.	cspec
PP5	N/A	The ATM VCEP framework marks PP5 as not applicable.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BA1 threshold of greater than 0.5%. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BS1 threshold of greater than 0.05%. BS1 is not met.	cspec gnomad_v4
BS2	N/A	The ATM VCEP framework marks BS2 as not applicable.	cspec
BS3	Not assessed	An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not show the specific rescue results for ATM-specific activity and radiosensitivity required to assign ATM BS3.	cspec vcep_suppl_tables1_pmid_40580951
BS4	N/A	The ATM VCEP framework marks BS4 as not applicable.	cspec
BP1	N/A	The ATM VCEP framework marks BP1 as not applicable.	cspec
BP2	Not assessed	No co-occurrence data in trans with a pathogenic ATM variant in unaffected individuals were identified, so BP2 points cannot be assigned.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM VCEP framework marks BP3 as not applicable.	cspec
BP4	Not met	Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, the REVEL score is 0.815, which is well above the ATM BP4 missense threshold of less than or equal to 0.249. Available computational evidence does not support BP4.	cspec revel spliceai
BP5	N/A	The ATM VCEP framework marks BP5 as not applicable.	cspec
BP6	N/A	The ATM VCEP framework marks BP6 as not applicable.	cspec
BP7	N/A	ATM BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect, and this variant is a missense substitution.	cspec

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