NM_000051.4:c.3137T>C

ATM · NP_000042.3:p.(Leu1046Pro) · NM_000051.4

GRCh37: chr11:108143318 T>C · GRCh38: chr11:108272591 T>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Pathogenic

PP3

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1046Pro)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles; 0 homozygotes), with the highest observed frequency in the South Asian population at 2.19587e-05 (2/91080 alleles; 0 homozygotes).

In silico evidence supports a deleterious missense effect, with REVEL 0.854 exceeding the ATM PP3 threshold of 0.7333, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).

Final determination: Under the ATM HBOP VCEP v1.5 final-classification framework, one pathogenic supporting criterion (PP3) is sufficient for a likely pathogenic classification.

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	This is a missense variant and does not create a premature termination codon or affect a canonical ±1,2 splice site, so the ATM PVS1 framework does not support applying PVS1.	pvs1_variant_assessment.json pvs1_gene_context.json vcep_materials.json
PS1	Not met	No pathogenic or likely pathogenic ATM variant producing the same amino acid change was identified in the available disease databases or ATM PS1 materials, so PS1 is not met.	evidence.json vcep_materials.json
PS2	N/A	The ATM CSPEC marks PS2 as not applicable for this framework.	case_summary.json
PS3	Not assessed	No variant-specific ATM functional study was identified showing failure to rescue both an ATM-specific function and radiosensitivity, so PS3 was not assessed.	vcep_materials.json clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx
PS4	Not assessed	No case-control data or statistically significant enrichment data for this variant were identified, so PS4 was not assessed.	case_summary.json literature_pass.json
PM1	N/A	The ATM CSPEC marks PM1 as not applicable for this framework.	case_summary.json
PM2	Not met	This variant is absent from gnomAD v2.1 and is very rare in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles), but the highest observed South Asian frequency is 2.19587e-05 (0.00220%; 2/91080), which is above the ATM PM2_Supporting threshold of 0.001%, so PM2 was not applied.	case_summary.json evidence.json
PM3	Not assessed	No observations of this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 was not assessed.	vcep_materials.json literature_pass.json
PM4	N/A	This is not a stop-loss variant, so PM4 is not applicable.	case_summary.json
PM5	N/A	The ATM PM5 specification is limited to truncating or qualifying splice variants upstream of p.Arg3047, so it does not apply to this missense variant.	case_summary.json
PM6	N/A	The ATM CSPEC marks PM6 as not applicable for this framework.	case_summary.json
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	literature_pass.json case_summary.json
PP2	N/A	The ATM CSPEC marks PP2 as not applicable for this framework.	case_summary.json
PP3	Met	In silico evidence supports a deleterious missense effect: the REVEL score is 0.854, which is above the ATM PP3 threshold of 0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.	prefetch.json evidence.json case_summary.json
PP4	N/A	The ATM CSPEC marks PP4 as not applicable for this framework.	case_summary.json
PP5	N/A	The ATM CSPEC marks PP5 as not applicable for this framework.	case_summary.json
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BA1 threshold of 0.5%, so BA1 is not met.	case_summary.json evidence.json
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BS1 threshold of 0.05%, so BS1 is not met.	case_summary.json evidence.json
BS2	N/A	The ATM CSPEC marks BS2 as not applicable for this framework.	case_summary.json
BS3	Not assessed	No variant-specific ATM functional study was identified showing rescue of ATM-specific function or radiosensitivity, so BS3 was not assessed.	vcep_materials.json clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx
BS4	N/A	The ATM CSPEC marks BS4 as not applicable for this framework.	case_summary.json
BP1	N/A	The ATM CSPEC marks BP1 as not applicable for this framework.	case_summary.json
BP2	Not assessed	No co-occurrence data were identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-ataxia-telangiectasia setting, so BP2 was not assessed.	vcep_materials.json literature_pass.json
BP3	N/A	The ATM CSPEC marks BP3 as not applicable for this framework.	case_summary.json
BP4	Not met	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1, but the REVEL score is 0.854, which is above the ATM BP4 missense threshold of 0.249, so BP4 is not met.	prefetch.json evidence.json case_summary.json
BP5	N/A	The ATM CSPEC marks BP5 as not applicable for this framework.	case_summary.json
BP6	N/A	The ATM CSPEC marks BP6 as not applicable for this framework.	case_summary.json
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic variant, so BP7 is not applicable.	case_summary.json evidence.json

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.