NM_000051.4:c.8292_8293del

ATM · NP_000042.3:p.(Ser2764ArgfsTer4) · NM_000051.4

GRCh37: chr11:108213970 AGT>A · GRCh38: chr11:108343243 AGT>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ser2764ArgfsTer4)

gnomAD AF

1.858874265744665e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

Pathogenic: the ATM frameshift meets the VCEP's very-strong PVS1 truncation rule.

Pathogenic evidence: PM2 supporting is met by the very low gnomAD v4.1 frequency.

Pathogenic evidence: PM5 supporting is met because termination occurs upstream of the ATM 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: the frameshift terminates at approximately p.2767, upstream of ATM's p.Arg3047 pathogenic truncation boundary.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	N/A	Not applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP PS1 scope for same-amino-acid missense or qualifying splice-region comparisons.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 for both ATM autosomal-dominant and autosomal-recessive disease contexts.	cspec
PS3	Not assessed	Not assessed: no qualifying ATM-specific assay result was documented for c.8292_8293del, so the VCEP PS3 strength thresholds cannot be applied.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no qualifying case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval was available for this exact variant.	cspec PMID:23807571 PMID:25614872 PMID:31050087
PM1	N/A	Not applicable: ATM VCEP v1.5 marks PM1 not applicable, and frameshift p.(Ser2764ArgfsTer4) is not a missense domain or hotspot observation.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 total AF is 1.858874e-6 (0.0001859%), below the ATM VCEP PM2 threshold of <=0.001%.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation documents this variant with a second ATM pathogenic variant in trans or qualifying homozygosity for PM3 points.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, whereas this variant is a frameshift with a premature termination signal.	cspec vcep_atm_pvs1_1_5
PM5	Met	Met, supporting: p.(Ser2764ArgfsTer4) is a frameshift termination upstream of the ATM VCEP PM5 cutoff at p.Arg3047.	cspec
PM6	N/A	Not applicable: the ATM VCEP excludes PM6 for both ATM autosomal-dominant and autosomal-recessive disease contexts.	cspec
PP1	Not assessed	Not assessed: zero affected-relative segregations are documented, versus the ATM VCEP threshold of one affected relative for PP1 supporting.	cspec PMID:23807571 PMID:25614872
PP2	N/A	Not applicable: ATM VCEP v1.5 marks PP2 not applicable, and this variant is a frameshift rather than a missense substitution.	cspec
PP3	N/A	Not applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP PP3 scope for missense or splice-region/intronic variants.	cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: ATM VCEP 1.5 prohibits separate PP4 use for breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2.	cspec
PP5	N/A	Not applicable: ATM VCEP 1.5 does not use PP5, and ClinVar lists zero expert-panel submissions for this exact variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 6.8e-7 (0.000068%), below the ATM VCEP BA1 threshold of >0.5%.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 6.8e-7 (0.000068%), below the ATM VCEP BS1 threshold of >0.05%.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP v1.5 explicitly excludes BS2, regardless of the gnomAD v4.1 homozygote count of 0.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific rescue of ATM function or radiosensitivity was documented, so the VCEP BS3 thresholds cannot be applied.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: BS4 is excluded by the ATM VCEP version 1.5 specification.	cspec
BP1	N/A	Not applicable: ATM VCEP v1.5 marks BP1 not applicable, and this variant is a frameshift rather than a missense substitution.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrying this variant with a pathogenic ATM variant in trans or qualifying homozygosity is documented.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable, and this variant is a truncating frameshift rather than an in-frame repeat-region indel.	cspec vcep_atm_pvs1_1_5
BP4	N/A	Not applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP BP4 scope for missense or splice-region/intronic variants.	cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: ATM VCEP 1.5 prohibits BP5 because co-occurring pathogenic variants and similar phenotypes are recognized in this disease context.	cspec
BP6	N/A	Not applicable: ATM VCEP 1.5 prohibits BP6, and ClinVar lists zero expert-panel submissions for this exact variant.	cspec clinvar
BP7	N/A	Not applicable: frameshift p.(Ser2764ArgfsTer4) is not a synonymous or qualifying deep-intronic variant within ATM VCEP BP7 scope.	cspec

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