Variant classification summary

NM_000051.4:c.4231del

ATM · NP_000042.3:p.(Ser1411AlafsTer40) · NM_000051.4

GRCh37: chr11:108159821 CA>C · GRCh38: chr11:108289094 CA>C

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.(Ser1411AlafsTer40)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): out-of-frame deletion creating premature stop p.(Ser1411AlafsTer40), predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% threshold.

3

PM5 (Supporting): premature stop at residue ~1450, upstream of the p.Arg3047 truncation cutoff.

4

Final: Pathogenic, via VCEP Rule4 — PVS1 very strong combined with PM2 and PM5 supporting.

Final determination: Rule4 of the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 (CSPEC doc 639508985) is satisfied: exactly 1 Pathogenic.Very Strong criterion (PVS1) together with >=2 Pathogenic.Supporting criteria (PM2 supporting, PM5 supporting), therefore 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	Met at Very Strong: out-of-frame deletion creating premature stop p.(Ser1411AlafsTer40), predicted to trigger nonsense-mediated decay.	vcep_atm_pvs1_1_5 cspec pvs1_generic_framework
PS1	N/A	Not applicable: PS1 applies only to missense or splice-region variants; c.4231del is a frameshift.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: ataxia-telangiectasia is autosomal recessive, so de novo occurrences are not informative under the ATM VCEP.	cspec
PS3	Not assessed	Not assessed: insufficient evidence was available, as no VCEP-approved functional assay is documented to have tested c.4231del.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:23807571 PMID:25614872
PS4	Not assessed	Not assessed: no case-control study of this exact variant was available, so no odds ratio or p-value could be computed.	PMID:23807571 PMID:25614872 cspec
PM1	N/A	Not applicable: the ATM VCEP disallows PM1 because germline mutational hotspots are not well defined for this gene.	cspec vcep_atm_pvs1_1_5
PM2	Met	Met at Supporting: completely absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% frequency threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no proband-level data (zygosity, phase, or phenotype) existed for c.4231del, so no PM3 points could be scored.	vcep_atm_pm3_bp2_1_5 clinvar PMID:23807571 PMID:25614872 gnomad_v4
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants; c.4231del is an out-of-frame frameshift with a premature stop.	cspec
PM5	Met	Met at Supporting: premature stop at residue ~1450, upstream of the p.Arg3047 truncation cutoff for pathogenic ATM variants.	cspec pm5_candidates pvs1_variant_assessment vcep_atm_pvs1_1_5
PM6	N/A	Not applicable: ataxia-telangiectasia is autosomal recessive, so assumed de novo occurrences are not informative under the ATM VCEP.	cspec
PP1	Not assessed	Not assessed: no family or segregation data for c.4231del were available.	cspec clinvar PMID:23807571 PMID:25614872
PP2	N/A	Not applicable: the ATM VCEP disallows PP2, as ATM lacks a defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.01, far below the >=0.2 VCEP threshold.	spliceai cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP routes phenotype evidence through its PM3/BP2 points system instead of PP4.	cspec vcep_atm_pm3_bp2_1_5
PP5	N/A	Not applicable: no ClinVar expert-panel (3-star) classification of this variant exists to trigger PP5.	clinvar cspec
BA1	Not met	Not met: absent from gnomAD v4.1 (AF=0), far below the >0.5% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v4.1 (AF=0), below the >0.05% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 not applicable; unaffected-carrier data is handled by its PM3/BP2 system.	cspec
BS3	Not assessed	Not assessed: insufficient evidence was available, as no rescue or complementation assay data for c.4231del exist.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:23807571 PMID:25614872
BS4	N/A	Not applicable: the ATM VCEP disallows BS4 for autosomal recessive conditions like ataxia-telangiectasia.	cspec
BP1	N/A	Not applicable: the ATM VCEP disallows BP1, as pathogenic missense variants are known in this gene.	cspec
BP2	Not assessed	Not assessed: no unaffected-carrier observations with phase information for c.4231del were available.	vcep_atm_pm3_bp2_1_5 clinvar PMID:23807571 PMID:25614872 gnomad_v4
BP3	N/A	Not applicable: BP3 covers in-frame indels in repetitive regions; c.4231del is an out-of-frame deletion.	cspec
BP4	Not met	Not met: a clean SpliceAI score (max delta 0.01) does not negate the variant's established frameshift truncation effect.	spliceai cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP explicitly lists BP5 as not applicable.	cspec
BP6	N/A	Not applicable: no ClinVar expert-panel (3-star) benign classification of this variant exists to trigger BP6.	clinvar cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous and deep intronic variants; c.4231del is a coding frameshift deletion.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.