Variant classification summary

NM_000051.4:c.2377-18T>C

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108129695 T>C · GRCh38: chr11:108258968 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

9.389636095263492e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: SpliceAI maximum delta 0.059 is below the ATM VCEP threshold of 0.1 for no predicted splice impact.

Final determination: Because only one supporting benign criterion (BP4) is applied and no ATM VCEP pathogenic or benign combination rule is met, 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	Not met	Not met: the intronic -18 variant is outside canonical splice positions, lacks RNA evidence, and has SpliceAI maximum delta 0.059.	cspec spliceai vcep_atm_pvs1_1_5
PS1	Not assessed	Not assessed: SpliceAI max delta is 0.059, but no qualifying same-event P/LP reference entry was found for PS1 comparison.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	Not applicable: the ATM VCEP v1.6 explicitly excludes PS2 for autosomal-dominant and autosomal-recessive ATM disease.	cspec
PS3	Not assessed	Not assessed: no variant-specific ATM kinase or radiosensitivity result was found in the governing approved-assay sources for c.2377-18T>C.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no variant-specific case-control p-value, effect estimate, or confidence interval is available to evaluate the ATM PS4 thresholds.	cspec
PM1	N/A	Not applicable: ATM VCEP marks PM1 not applicable, and this intronic variant has protein consequence p.? rather than a codon residue.	cspec
PM2	Not met	Not met: gnomAD v4.1 East Asian AF is 2.2346e-05 (0.00223%), above the ATM VCEP PM2 threshold of <=0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, homozygous, second-allele, or phase evidence is available to assign the ATM VCEP's PM3 points.	vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: PM4 is reserved for stop-loss variants, whereas this intronic variant has protein annotation p.? and no protein-length change.	cspec
PM5	N/A	Not applicable: ATM PM5 is restricted to qualifying truncating or observed NMD-prone splice variants, whereas this variant is c.2377-18T>C with p.?.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP v1.6 explicitly excludes PM6 for autosomal-dominant and autosomal-recessive ATM disease.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation, parental testing, phase, or meiosis data are documented to meet the ATM PP1 thresholds.	cspec
PP2	N/A	Not applicable: ATM VCEP marks PP2 not applicable, and the variant is intronic with protein consequence p.? rather than missense.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.059 is below the ATM VCEP PP3 splicing threshold of >=0.2.	cspec spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP prohibits separate PP4 use for both ATM-related cancer predisposition and ataxia-telangiectasia.	cspec
PP5	N/A	Not applicable: ATM prohibits PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 5.49e-06, below the ATM VCEP BA1 threshold of >0.005.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 5.49e-06, below the ATM VCEP BS1 threshold of >0.0005.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM-related disease has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: no variant-specific ATM rescue or normal-function result was found in the governing approved-assay sources for c.2377-18T>C.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: the ATM VCEP v1.6 excludes BS4 because informative non-segregation in ataxia-telangiectasia families is too rare.	cspec
BP1	N/A	Not applicable: ATM VCEP marks BP1 not applicable, and this variant is intronic with protein consequence p.? rather than missense.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrying this variant with a pathogenic ATM allele in trans or qualifying homozygous observation is documented.	vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP explicitly designates BP3 as Not Applicable for this framework.	cspec
BP4	Met	Met at supporting: SpliceAI maximum delta 0.059 meets the ATM VCEP BP4 splicing threshold of <=0.1.	cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because co-occurring pathogenic variants are common and may not alter the phenotype.	cspec
BP6	N/A	Not applicable: ATM prohibits BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.2377-18T>C is intronic, whereas BP7 applies only to synonymous variants.	cspec

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