LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_000051.4_c.4306C_T_20261106_152112
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.4306C>T

ATM  · NP_000042.3:p.(His1436Tyr)  · NM_000051.4
GRCh37: chr11:108160398 C>T  ·  GRCh38: chr11:108289671 C>T
Gene: ATM Transcript: NM_000051.4
Final call
VUS
BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(His1436Tyr)
gnomAD AF
2.727958098563606e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BP4 Supporting: the missense REVEL score is 0.166, below the ATM VCEP cutoff of 0.249.
Final determination: Because BP4 Supporting alone satisfies neither a pathogenic nor a benign ATM VCEP combination rule, the classification remains 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: c.4306C>T is a missense change, whereas the ATM PVS1 rule applies to specified null-variant classes.
vcep_atm_pvs1_1_6 cspec pvs1_variant_assessment
PS1 Not met Not met: ATM_PS1_1.6.pdf contains no entry for c.4306C>T, p.His1436Tyr, or p.H1436Y, and exact-variant reports classify it as VUS rather than pathogenic.
cspec vcep_atm_ps1_1_6 PMID:32066632 PMID:32325837 PMID:36555667
PS2 N/A Not applicable: the ATM VCEP v1.6 specification explicitly marks PS2 as Not Applicable.
cspec
PS3 Not assessed Not assessed: Table S1 labels c.4306C>T Functional but DeepATM_predicted=Yes, so it is computational and cannot provide PS3 functional evidence.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4 Not met Not met: one case and one control carrier gave OR 2.16, but Fisher p=0.537 and the 95% CI lower bound 0.133 failed the VCEP thresholds.
cspec PMID:32066632 PMID:28779002 PMID:34262154
PM1 N/A Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined.
cspec
PM2 Not met Not met: the highest gnomAD v4.1 subpopulation AF is 0.00400%, exceeding the VCEP PM2 threshold of at most 0.001%.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no A-T proband with a documented pathogenic variant in trans or VCEP-assigned PM3 points is available for ATM c.4306C>T.
cspec vcep_atm_pm3_bp2_1_6 PMID:32066632 PMID:32325837 PMID:36555667
PM4 N/A Not applicable: p.(His1436Tyr) is a missense substitution, not the stop-loss variant type named by the ATM PM4 rule.
cspec pvs1_variant_assessment
PM5 N/A Not applicable: the ATM PM5 rule is limited to NMD-prone truncating variants, whereas c.4306C>T produces the missense change p.His1436Tyr.
cspec
PM6 N/A Not applicable: the ATM VCEP v1.6 specification explicitly marks PM6 as Not Applicable.
cspec
PP1 Not assessed Not assessed: no affected-relative segregation or co-segregation data are reported, so the VCEP's 1-, 2-, or 3-relative PP1 thresholds cannot be evaluated.
cspec PMID:32066632 PMID:32325837
PP2 N/A Not applicable: the ATM VCEP prohibits PP2 because ATM does not have a defined low rate of benign missense variation.
cspec
PP3 Not met Not met: REVEL 0.166 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.075 is below the >=0.2 threshold.
cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4 N/A Not applicable: the ATM VCEP excludes PP4 for dominant cancer predisposition and does not allow it separately for recessive ataxia-telangiectasia.
cspec
PP5 N/A Not applicable: the ATM VCEP explicitly prohibits PP5, regardless of general review statements or ClinVar classifications.
cspec
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.002475%, below the VCEP BA1 threshold of greater than 0.5%.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.002475%, below the VCEP BS1 threshold of greater than 0.05%.
cspec gnomad_v2 gnomad_v4
BS2 N/A Not applicable: the ATM VCEP explicitly marks BS2 as Not Applicable.
cspec
BS3 Not assessed Not assessed: Table S1 labels c.4306C>T Functional but DeepATM_predicted=Yes, so it is computational and cannot provide BS3 functional evidence.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4 N/A Not applicable: the ATM VCEP v1.6 specification explicitly marks BS4 as Not Applicable.
cspec
BP1 N/A Not applicable: the ATM VCEP prohibits BP1 because missense pathogenic variants are known for ATM.
cspec
BP2 Not assessed Not assessed: no qualifying unaffected adult observation with confirmed phase and a pathogenic ATM allele is documented for ATM c.4306C>T.
cspec vcep_atm_pm3_bp2_1_6 PMID:32066632 PMID:32325837 PMID:36555667
BP3 N/A Not applicable: the ATM VCEP marks BP3 not applicable, and this variant is a missense substitution rather than an in-frame indel.
cspec pvs1_variant_assessment
BP4 Met Met at Supporting: missense REVEL 0.166 is below the VCEP BP4 cutoff of <=0.249.
cspec revel vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5 N/A Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants may coexist without a noticeable phenotype difference and ATM has low penetrance.
cspec
BP6 N/A Not applicable: the ATM VCEP explicitly prohibits BP6, regardless of benign assertions from ClinVar or published sources.
cspec
BP7 N/A Not applicable: BP7 is restricted to synonymous or qualifying deep intronic variants, while c.4306C>T is missense.
cspec
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