Variant classification summary

NM_000051.4:c.3332T>C

ATM · NP_000042.3:p.(Leu1111Pro) · NM_000051.4

GRCh37: chr11:108150265 T>C · GRCh38: chr11:108279538 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1111Pro)

gnomAD AF

3.0984309545646086e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 allele frequency 0.00031% (3.1e-06), below the <=0.001% threshold, with no observed homozygotes.

2

Overall classification: VUS - only PM2 (Supporting) was met, insufficient for any pathogenic or benign rule under the ATM VCEP v1.5 combination framework.

Final determination: No VCEP rule satisfied by a single PM2_Supporting criterion → VUS.

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	Not applicable: this is a missense substitution, and the ATM VCEP restricts PVS1 to null variants such as nonsense, frameshift, and canonical splice-site changes.	cspec spliceai
PS1	Not met	Not met: no established pathogenic or likely pathogenic variant producing the same p.Leu1111Pro amino-acid change was found.	vcep_atm_ps1_1_5 pm5_candidates
PS2	N/A	Not applicable: the ATM VCEP specifies PS2 is not used for ATM-related disease because informative de novo occurrences are lacking.	cspec
PS3	Not assessed	Not assessed: no VCEP-approved assay result exists; a 2025 screen reporting normal function is flagged for human review as it is not VCEP-calibrated.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:40580951 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no case-control study with a qualifying odds ratio or p-value for this variant was available.	cspec
PM1	N/A	Not applicable: the ATM VCEP explicitly marks the hotspot/functional-domain criterion PM1 as not used for ATM.	cspec
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 0.00031% (3.1e-06), below the <=0.001% PM2 threshold, with no observed homozygotes.	cspec gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observation or second pathogenic ATM variant in trans was documented.	cspec vcep_atm_pm3_bp2_1_5 clinvar
PM4	N/A	Not applicable: this is a missense substitution, and the ATM VCEP restricts PM4 to stop-loss variants.	cspec
PM5	N/A	Not applicable: the ATM VCEP restricts PM5 to truncating variants and explicitly disallows it for missense changes.	cspec
PM6	N/A	Not applicable: the ATM VCEP specifies PM6 is not used for ATM-related disease.	cspec
PP1	Not assessed	Not assessed: no affected relatives, parental testing, or other segregation observations were documented.	cspec
PP2	N/A	Not applicable: the ATM VCEP explicitly marks the missense-constraint criterion PP2 as not used for ATM.	cspec
PP3	Not met	Not met: REVEL 0.644, below the >0.7333 threshold required for missense variants.	revel spliceai cspec
PP4	N/A	Not applicable: the ATM VCEP marks PP4 as not used because phenotypes do not distinguish hereditary from sporadic causes.	cspec
PP5	N/A	Not applicable: the ATM VCEP marks PP5 as not used, and no expert-panel pathogenic ClinVar classification exists for this variant.	cspec clinvar
BA1	Not met	Not met: grpmax filtering allele frequency 0.000124% (1.24e-06), far below the >0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: grpmax filtering allele frequency 0.000124% (1.24e-06), below the >0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 as not used.	cspec
BS3	Not assessed	Not assessed: no VCEP-approved assay result exists; a 2025 screen reporting normal function is flagged for human review as it is not VCEP-calibrated.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:40580951 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: the ATM VCEP specifies BS4 is not used because informative lack-of-segregation instances are too rare.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 as not used because mutational hotspots are not well defined in ATM.	cspec
BP2	Not assessed	Not assessed: no unaffected carrier with a pathogenic ATM variant in trans or phase information was documented.	cspec vcep_atm_pm3_bp2_1_5 clinvar
BP3	N/A	Not applicable: the ATM VCEP marks BP3 as not used, and it does not apply to missense substitutions.	cspec
BP4	Not met	Not met: REVEL 0.644 lies above the <=0.249 BP4 threshold (gray zone between BP4 and PP3).	revel spliceai cspec bayesdel
BP5	N/A	Not applicable: the ATM VCEP marks BP5 as not used because ATM has low penetrance and phenotype differences are unclear.	cspec
BP6	N/A	Not applicable: the ATM VCEP marks BP6 as not used, and no expert-panel benign ClinVar classification exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous and deep intronic variants, and this is a missense substitution.	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.