Variant classification summary

NM_000051.4:c.7243G>C

ATM · NP_000042.3:p.(Ala2415Pro) · NM_000051.4

GRCh37: chr11:108199901 G>C · GRCh38: chr11:108329174 G>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.(Ala2415Pro)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v4.1, satisfying the <=0.001% rarity threshold.

2

Overall classification: VUS, as the sole PM2 (Supporting) criterion satisfies no pathogenic or benign combination rule.

Final determination: No ATM HBOP VCEP v1.5 criteria-combination rule is met by PM2 Supporting alone; therefore the variant remains a Variant of 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	Not met	Not met: p.Ala2415Pro is a missense change, not a null variant, and SpliceAI max delta 0.012 shows no splice impact.	cspec vcep_atm_pvs1_1_5 spliceai
PS1	Not met	Not met: no pathogenic comparator with the same p.Ala2415Pro change exists; the only ClinVar entry is a single-submitter VUS.	cspec clinvar spliceai
PS2	N/A	Not applicable: the ATM VCEP prohibits PS2 because informative de novo occurrences have not been observed.	cspec
PS3	Not assessed	Not assessed: a research screen predicts loss of function, but it is not a VCEP-approved assay and awaits human review.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec
PS4	Not assessed	Not assessed: no case-control enrichment study for this exact variant was identified.	cspec PMID:25394175
PM1	N/A	Not applicable: the ATM VCEP provides no approved domain list, so PM1 cannot be applied to residue 2415.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1, satisfying the <=0.001% PM2 rarity threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband, second ATM variant, or phase/in-trans evidence was documented.	cspec vcep_atm_pm3_bp2_1_5
PM4	Not met	Not met: PM4 is restricted to stop-loss variants, and p.Ala2415Pro does not alter protein length.	cspec
PM5	N/A	Not applicable: PM5 applies only to truncating or frameshifting variants, not this missense change.	cspec
PM6	N/A	Not applicable: the ATM VCEP prohibits PM6 because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: no segregation data in affected relatives were available for this variant.	cspec
PP2	N/A	Not applicable: the ATM VCEP framework provides no PP2 missense-mechanism rule.	cspec
PP3	Not met	Not met: REVEL 0.512 falls below the >0.7333 threshold and SpliceAI max delta 0.012 below 0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: PP4 is designated Not Applicable in the ATM VCEP specification.	cspec
PP5	N/A	Not applicable: designated so by the ATM VCEP, and no expert-panel ClinVar assertion exists for this variant.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v4.1, far below the >0.5% stand-alone benign frequency threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v4.1, below the >0.05% BS1 frequency threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	N/A	Not applicable: BS2 is marked Not Applicable by the ATM VCEP.	cspec
BS3	Not assessed	Not assessed: no validated benign functional result was available; the research assay instead predicts loss of function.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec
BS4	N/A	Not applicable: BS4 is marked Not Applicable by the ATM VCEP.	cspec
BP1	N/A	Not applicable: the ATM VCEP provides no BP1 rule for a low-impact missense region.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected-carrier co-occurrence or phase data were available.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: BP3 is designated Not Applicable in the ATM VCEP specification.	cspec
BP4	Not met	Not met: REVEL 0.512 exceeds the <=0.249 threshold required by the laboratory's missense BP4 rule.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: BP5 is designated Not Applicable in the ATM VCEP specification.	cspec
BP6	N/A	Not applicable: designated so by the ATM VCEP, and no expert-panel benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous or deep-intronic variants, not this missense change.	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.