Variant classification summary

NM_000051.4:c.5890A>G

ATM · NP_000042.3:p.(Lys1964Glu) · NM_000051.4

GRCh37: chr11:108181014 A>G · GRCh38: chr11:108310287 A>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Lys1964Glu)

gnomAD AF

7.561492911410293e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 Supporting is met because REVEL is 0.207 and SpliceAI maximum delta is 0.021, both within the VCEP benign-prediction thresholds.

Final determination: Under the ATM VCEP Version 1.6 ACMG/AMP combination rules, no pathogenic or benign rule is satisfied by BP4 Supporting alone, so 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.5890A>G is a missense substitution, whereas the VCEP PVS1 rule is limited to listed null variant classes.	cspec vcep_atm_pvs1_1_6 pvs1_variant_assessment
PS1	Not assessed	Not assessed: no ATM_PS1_1.6 table entry or established pathogenic same-amino-acid comparator was found for p.Lys1964Glu.	cspec vcep_atm_ps1_1_6
PS2	N/A	Not applicable: the ATM VCEP specification explicitly marks PS2 as Not Applicable.	cspec
PS3	Not assessed	Not assessed: the exact S1 row is a computational prediction (DeepATM_predicted=Yes), not a direct assay result, so PS3 cannot be assigned.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS4	Not assessed	Not assessed: available case-control papers lack variant-specific case/control counts or an effect estimate and p-value for ATM c.5890A>G.	cspec PMID:19781682 PMID:21787400 PMID:23555315 PMID:17508274 PMID:26324357
PM1	N/A	Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and hotspots are not well defined.	cspec
PM2	Not met	Not met: the highest gnomAD v4.1 subpopulation AF is 0.0822368%, above the VCEP PM2 threshold of ≤0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no governing-table entry or qualifying affected-proband, phase, or pathogenic-in-trans observation is available to assign PM3 points.	cspec vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: p.Lys1964Glu is a missense substitution and does not create the stop-loss protein-length change required by the VCEP.	cspec
PM5	N/A	Not applicable: the ATM VCEP explicitly excludes missense changes from PM5 because same-residue substitutions may be pathogenic or benign.	cspec
PM6	N/A	Not applicable: the ATM VCEP specification explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation count or qualifying autosomal-recessive phenotype is documented for the variant.	cspec PMID:21787400
PP2	N/A	Not applicable: the ATM VCEP states that ATM lacks a defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: REVEL 0.207 is below the VCEP PP3 cutoff >0.7333 and SpliceAI maximum delta 0.021 is below ≥0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP excludes PP4 for hereditary breast cancer and incorporates autosomal-recessive phenotype evidence into PM3/BP2.	cspec
PP5	N/A	Not applicable: the ATM VCEP prohibits PP5 use, regardless of external reports of pathogenicity.	cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.032328%, below the VCEP BA1 threshold of >0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.032328%, below the VCEP BS1 threshold of >0.05%.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: the exact S1 row is a computational prediction (DeepATM_predicted=Yes), not a direct assay result, so BS3 cannot be assigned.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:40580951
BS4	N/A	Not applicable: the ATM VCEP specification explicitly marks BS4 as Not Applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP excludes BP1 because missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	Not assessed: no governing-table entry or qualifying unaffected-adult observation with a pathogenic variant and documented cis/trans phase is available for BP2.	cspec vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable and instructs that it must not be used; this variant is missense.	cspec
BP4	Met	Met at Supporting: REVEL 0.207 is within the VCEP BP4 missense threshold of ≤0.249, with concordant SpliceAI maximum delta 0.021.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants can occur without a noticeable phenotype difference.	cspec
BP6	N/A	Not applicable: the ATM VCEP prohibits BP6 use, regardless of external reports of benignity.	cspec
BP7	N/A	Not applicable: c.5890A>G is a missense exon 39 variant, whereas the VCEP BP7 scope is synonymous or deep intronic variants.	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.