Variant classification summary

NM_000051.4:c.4394T>C

ATM · NP_000042.3:p.(Leu1465Pro) · NM_000051.4

GRCh37: chr11:108160486 T>C · GRCh38: chr11:108289759 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PS3 supporting PM2 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1465Pro)

gnomAD AF

1.2394952775229927e-06 (v4.1)

ClinVar

Likely Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Supporting): Barone 2009 showed this exact variant retains reduced ATM kinase activity in a VCEP-approved assay.

2

PM2 (Supporting): gnomAD v4.1 frequency 0.000124% is below the 0.001% threshold.

3

PP5 (Supporting): the ClinGen HBOP expert panel classified this exact variant as likely pathogenic.

4

Final classification: VUS — three supporting criteria (PS3, PM2, PP5) do not satisfy any VCEP combination rule.

Final determination: No ATM VCEP v1.5 mainRules combination matches PS3_Supporting + PM2_Supporting + PP5_Supporting, so the variant is Uncertain Significance.

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 PVS1 applies only to null variants under the ATM VCEP rule.	pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not met	Not met: no other nucleotide change producing the same p.(Leu1465Pro) substitution has been classified pathogenic or likely pathogenic.	clinvar pm5_candidates vcep_atm_ps1_1_5 cspec
PS2	N/A	Not applicable under the ATM VCEP v1.5 specification.	cspec
PS3	Met	Met (supporting): Barone 2009 tested this exact variant and showed reduced ATM kinase activity, per the VCEP-approved assay.	PMID:19431188 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec
PS4	Not assessed	Not assessed: no case-control enrichment study of this exact variant met the VCEP threshold (p <= 0.05, OR/HR/RR >= 2).	cspec
PM1	N/A	Not applicable: the ATM VCEP marks PM1 out of use because benign and pathogenic variants share the same functional domains.	cspec
PM2	Met	Met (supporting): gnomAD v4.1 frequency 0.000124% is below the VCEP's 0.001% PM2 threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected individual with a second ATM variant, phase, or phenotype data was available.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: PM4 applies only to stop-loss variants, and this is a missense substitution.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the ATM VCEP defines PM5 as a truncation-cutoff rule, which a missense substitution cannot meet.	cspec pm5_candidates
PM6	N/A	Not applicable under the ATM VCEP v1.5 specification.	cspec
PP1	Not assessed	Not assessed: no case-specific segregation data were available to meet the ATM VCEP autosomal-recessive PP1 thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 out of use, superseding the generic missense-based criterion.	cspec
PP3	Not met	Not met: REVEL 0.329 is well below the 0.7333 pathogenic threshold, and SpliceAI max delta 0.008 shows no splice impact.	cspec revel spliceai
PP4	N/A	Not applicable under the ATM VCEP v1.5 framework.	cspec
PP5	Met	Met (supporting): the ClinGen HBOP expert panel classified this exact variant as likely pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax frequency 0.000028% is far below the 0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax frequency 0.000028% is far below the 0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable under the ATM VCEP v1.5 framework.	cspec
BS3	Not met	Not met: the only approved functional assay showed reduced, not normal, kinase activity, which is inconsistent with BS3.	PMID:19431188 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable under the ATM VCEP v1.5 specification.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 out of use, superseding the generic missense-based criterion.	cspec
BP2	Not assessed	Not assessed: no unaffected individual carrying this variant with a second ATM variant or phase information was available.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP marks BP3 out of use, and the variant is not an in-frame indel.	cspec
BP4	Not met	Not met: REVEL 0.329 sits above the 0.249 benign threshold, leaving the missense effect unruled-out.	cspec revel spliceai
BP5	N/A	Not applicable under the ATM VCEP v1.5 framework.	cspec
BP6	Not met	Not met: no expert-panel benign or likely benign assertion exists; the only expert-panel call on this variant is likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous and deep intronic variants, not missense substitutions.	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.