Variant classification summary

NM_000051.3:c.8161G>A

ATM · NP_000042.3:p.(Asp2721Asn) · NM_000051.3

GRCh37: chr11:108206581 G>A · GRCh38: chr11:108335854 G>A

Gene: ATM Transcript: NM_000051.3

Final call

VUS

PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Asp2721Asn)

gnomAD AF

ClinVar

Likely Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.8161G>A (p.Asp2721Asn; p.D2721N) variant has been observed in somatic cancers (COSMIC COSV53771356, n=10) and has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as Likely Pathogenic.

2

This variant is absent from both gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the ATM PM2_Supporting frequency threshold of <=0.001%.

3

Available computational evidence supports a damaging missense effect: REVEL is 0.957, above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644; a VCEP-linked supplementary table scored the variant as non-functional with medium-high confidence; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.07.

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, initiation-codon, exon-level deletion, or canonical +/-1,2 splice variant, so the ATM PVS1 framework does not apply.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not assessed	No evidence was identified showing that this variant produces the same amino acid change as an established ATM pathogenic or likely pathogenic variant, and SpliceAI does not suggest an alternative splice-based PS1 scenario for this substitution.	cspec spliceai vcep_atm_ps1_1_5
PS2	N/A	The ATM VCEP marks PS2 as not applicable in this framework.	cspec
PS3	Not assessed	No ATM VCEP-approved functional study was identified showing that this variant fails to rescue an ATM-specific function or radiosensitivity. A VCEP-linked supplementary table scored the variant as non-functional, but this was not sufficient on its own to assign PS3 under the ATM functional evidence rules.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	This variant has been reported in ClinVar and in somatic cancer databases, but no case-control study or other enrichment data meeting the ATM PS4 threshold were identified.	cspec clinvar
PM1	N/A	The ATM VCEP marks PM1 as not applicable in this framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore 0, which is below the ATM PM2_Supporting threshold of <=0.001%.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia, so PM3 cannot be assigned from the available evidence.	cspec vcep_atm_pm3_bp2_1_5 clinvar
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 rule for qualifying truncating or certain splice variants upstream of p.Arg3047, not a classic same-residue missense rule. This missense variant does not meet that rule type.	cspec pm5_candidates
PM6	N/A	The ATM VCEP marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 cannot be assigned.	cspec clinvar
PP2	N/A	The ATM VCEP marks PP2 as not applicable in this framework.	cspec
PP3	Met	Available computational evidence supports a damaging missense effect. REVEL is 0.957, which is above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644, also favoring deleteriousness. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, supporting interpretation as a missense effect rather than a splice effect.	cspec revel bayesdel spliceai
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 Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BA1 threshold of >0.5%.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BS1 threshold of >0.05%.	cspec gnomad_v4
BS2	N/A	The ATM VCEP marks BS2 as not applicable in this framework.	cspec
BS3	Not assessed	No ATM VCEP-approved functional study was identified showing rescue of both an ATM-specific feature and radiosensitivity, or rescue of either one alone, for this variant. Therefore BS3 cannot be assigned from the available evidence.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
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 evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-A-T individual, so BP2 cannot be assigned.	cspec vcep_atm_pm3_bp2_1_5 clinvar
BP3	N/A	The ATM VCEP marks BP3 as not applicable in this framework.	cspec
BP4	Not met	BP4 is not met because the missense predictor threshold is not satisfied: REVEL is 0.957, which is above the ATM BP4 cutoff of <=0.249. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, the damaging missense prediction does not support a benign computational conclusion.	cspec revel spliceai
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	ATM BP7 is specified for synonymous or deep intronic variants without splice impact, and this variant is a missense substitution.	cspec spliceai

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