Variant classification summary

NM_000051.3:c.7031G>A

ATM · NP_000042.3:p.(Trp2344Ter) · NM_000051.3

GRCh37: chr11:108198427 G>A · GRCh38: chr11:108327700 G>A

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Trp2344Ter)

gnomAD AF

6.195871319187746e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports loss of function from the ATM nonsense variant p.(Trp2344Ter).

2

Pathogenic: PM2 supporting confirms the variant is below the ATM VCEP rarity threshold in gnomAD v4.1.

3

Pathogenic: PM5 supporting applies because the premature stop at p.Trp2344 is upstream of the ATM VCEP p.Arg3047 cutoff.

Final determination: ATM VCEP v1.5 Rule4 classifies a variant as Pathogenic when one Very Strong pathogenic criterion and at least two Supporting pathogenic criteria are met.

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	Met, very strong: c.7031G>A is a nonsense exon-48 variant truncating ATM at p.Trp2344, upstream of the p.Arg3047 C-terminal caution boundary.	cspec vcep_atm_pvs1_1_5 vcep_suppl_tables1_pmid_40580951
PS1	N/A	Not applicable: ATM PS1 covers missense or splice-region variants, whereas c.7031G>A is a nonsense variant producing p.(Trp2344Ter).	cspec vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	Not applicable: ATM VCEP version 1.5 prohibits PS2 for both autosomal dominant and autosomal recessive ATM disease.	cspec
PS3	Not assessed	Not assessed: direct measurement classified c.7031G>A as Non-functional with High confidence, but this assay is outside ATM VCEP-approved PS3 calibration.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	Not met: no case-control odds ratio, hazard ratio, or relative risk is reported for c.7031G>A, so the ATM VCEP requirement of OR >=2 with p <=.05 is unmet.	cspec clinvar PMID:25394175 PMID:24366376 PMID:25741868
PM1	N/A	Not applicable: the ATM VCEP marks PM1 not applicable, and no authoritative ATM domain-table entry is available for this nonsense variant.	cspec
PM2	Met	Met, supporting: gnomAD v4.1 total AF 0.00006196% is below the ATM VCEP PM2 threshold of <=0.001%, with one observed allele.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband, pathogenic variant in trans, or phase information is available to assign the VCEP's PM3 points.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
PM4	N/A	Not applicable: the ATM VCEP PM4 rule is restricted to stop-loss variants, whereas this variant is a premature-stop nonsense change.	cspec
PM5	Met	Met, Supporting: the truncating stop at p.Trp2344 is upstream of the ATM VCEP PM5 cutoff p.Arg3047.	cspec pm5_candidates
PM6	N/A	Not applicable: ATM VCEP version 1.5 prohibits PM6 for both autosomal dominant and autosomal recessive ATM disease.	cspec
PP1	Not assessed	Not assessed: no documented affected relatives or segregation results are available to meet the ATM VCEP's one-relative supporting threshold.	cspec
PP2	N/A	Not applicable: ATM PP2 is not applicable under the VCEP, and this variant is nonsense rather than missense.	cspec
PP3	N/A	Not applicable: c.7031G>A is a nonsense variant, outside ATM PP3's missense and splice-region/intronic scope despite SpliceAI max delta 0.057.	cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP v1.5 explicitly excludes PP4, so phenotype specificity cannot be scored for this variant.	cspec
PP5	Not met	Not met: ClinVar's five submissions for c.7031G>A are laboratory-level with zero expert-panel assertions, so the PP5 expert-panel condition is not satisfied.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 AF 0.00006196% is below the ATM VCEP BA1 threshold of >0.5%.	cspec gnomad_v4
BS1	Not met	Not met: the highest reported gnomAD v4.1 subpopulation AF is 0.001098%, below the ATM VCEP BS1 threshold of >0.05%.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly excludes BS2, despite zero homozygotes in gnomAD v4.1.	cspec gnomad_v4
BS3	Not met	Not met: direct prime-editing classification was Non-functional with High confidence, not a normal ATM functional-rescue result.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: ATM VCEP version 1.5 designates BS4 as not applicable.	cspec
BP1	N/A	Not applicable: ATM BP1 is not applicable under the VCEP, and this variant is a truncating nonsense change.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrying this variant with a pathogenic ATM variant in trans is documented for the VCEP's BP2 scoring.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
BP3	N/A	Not applicable: BP3 is excluded by the ATM VCEP, and this variant is a truncating nonsense allele rather than an in-frame repeat-region change.	cspec
BP4	N/A	Not applicable: c.7031G>A is a nonsense variant, outside ATM BP4's missense and splice-region/intronic scope; REVEL is unavailable and SpliceAI max delta is 0.057.	cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP v1.5 explicitly excludes BP5, defining no numeric threshold or comparison direction for this variant.	cspec
BP6	Not met	Not met: ClinVar has no expert-panel benign or likely benign assertion for c.7031G>A, so the BP6 expert-panel condition is not satisfied.	cspec clinvar
BP7	N/A	Not applicable: c.7031G>A is a nonsense variant, whereas ATM BP7 is restricted to synonymous or qualifying deep-intronic variants.	cspec vcep_suppl_tables1_pmid_40580951

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