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): the variant is absent from gnomAD v4.1, exceeding the <=0.001% supporting rarity threshold.

2

Final classification: VUS - PM2 (supporting) alone satisfies no pathogenic or benign combination rule in the ATM VCEP v1.5 framework.

Final determination: No criteria-combination rule in the ATM VCEP v1.5 framework is met by PM2 supporting alone; therefore the variant is classified as 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	Not met	Not met: c.7243G>C is a missense change (p.Ala2415Pro), not a null variant, and SpliceAI's max delta of 0.012 indicates no splice impact.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment spliceai
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same amino-acid change, p.Ala2415Pro, was available for comparison.	vcep_atm_ps1_1_5 cspec spliceai
PS2	N/A	Not applicable: the ATM VCEP framework does not use PS2 for ATM-related cancer predisposition or ataxia-telangiectasia.	cspec
PS3	Not assessed	Not assessed: a prime-editing screen scored this variant Non-functional, but PS3 awaits human review because that assay is not among the ATM VCEP's calibrated assays.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no case-control enrichment data for this exact variant met the required odds ratio >=2 with p<=0.05.	cspec PMID:25394175
PM1	N/A	Not applicable: the ATM VCEP excludes PM1 because benign and pathogenic variants occur within the same domains, with no defined germline hotspot.	cspec
PM2	Met	Met (supporting): the variant is absent from gnomAD v4.1, exceeding the VCEP's <=0.001% supporting rarity threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no proband phenotype, second ATM variant, zygosity, or phase data were available to score under the PM3 points framework.	cspec vcep_atm_pm3_bp2_1_5
PM4	Not met	Not met: PM4 applies only to stop-loss variants, and p.Ala2415Pro is a missense substitution with no protein-length change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the ATM VCEP prohibits PM5 for missense changes because same-residue substitutions can be pathogenic or benign.	cspec
PM6	N/A	Not applicable: the ATM VCEP framework does not use PM6 in either the cancer-predisposition or ataxia-telangiectasia context.	cspec
PP1	N/A	Not applicable: PP1 co-segregation is not used in the autosomal-dominant ATM cancer-predisposition context per the VCEP.	cspec
PP2	N/A	Not applicable: ATM lacks a defined low rate of benign missense variation, so PP2 does not apply.	cspec
PP3	Not met	Not met: REVEL 0.512 falls below the ATM VCEP PP3 threshold of >0.7333.	cspec revel spliceai
PP4	N/A	Not applicable: the ATM VCEP excludes PP4 because phenotypes such as breast cancer have multiple genetic etiologies that cannot be distinguished.	cspec
PP5	Not met	Not met: the sole ClinVar record is a single-submitter Uncertain significance from Ambry, with no expert-panel pathogenic assertion.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v4.1, so the >0.5% BA1 allele-frequency threshold is not reached.	cspec gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v4.1, so the >0.05% BS1 allele-frequency threshold is not reached.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP v1.5 framework does not apply BS2 to this variant.	cspec
BS3	Not met	Not met: the direct functional assay scored the variant Non-functional, showing no rescue of ATM function.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: no family-level observations of unaffected carriers or lack of segregation were available.	cspec
BP1	N/A	Not applicable: BP1 does not apply because pathogenic missense variants are well documented in ATM.	cspec
BP2	Not assessed	Not assessed: no unaffected-individual or in-trans allele data were available to score under the BP2 points framework.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP specification marks BP3 as not applicable.	cspec
BP4	Not met	Not met: REVEL 0.512 exceeds the <=0.249 BP4 threshold required for missense variants.	cspec revel spliceai
BP5	N/A	Not applicable: the ATM VCEP excludes BP5, as low ATM penetrance makes alternate-molecular-diagnosis reasoning unreliable.	cspec
BP6	Not met	Not met: the sole ClinVar submission is a single-submitter Uncertain significance, with no expert-panel benign assertion to support BP6.	clinvar
BP7	N/A	Not applicable: BP7 is limited to synonymous and deep-intronic variants, and this change is missense.	cspec spliceai

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.