Variant classification summary

NM_000051.4:c.4324T>C

ATM · NP_000042.3:p.(Tyr1442His) · NM_000051.4

GRCh37: chr11:108160416 T>C · GRCh38: chr11:108289689 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Tyr1442His)

gnomAD AF

0.0003910816040419616 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Overall classification: Uncertain Significance (VUS) - no ACMG/VCEP criterion was met, so no combination rule was satisfied.

Final determination: No ATM VCEP v1.5 combination rule is met since no criterion is in 'met' status, defaulting to VUS pending human review.

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: this is a missense substitution (p.Tyr1442His), and PVS1 applies only to null variants such as nonsense, frameshift, or splice-site changes.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same p.Tyr1442His change was available for comparison.	cspec clinvar oncokb
PS2	N/A	Not applicable: the ATM VCEP designates PS2 as not applicable, and no confirmed de novo occurrence is documented.	cspec
PS3	Not assessed	Not assessed: no VCEP-approved functional assay tested this variant, and a ClinVar submission notes functional studies are lacking.
PS4	Not assessed	Not assessed: reported in two contralateral breast-cancer and two CLL cases, but no case-control effect estimate met the p<=0.05, OR>=2 threshold.	cspec PMID:17393301 PMID:24172824
PM1	N/A	Not applicable: the ATM VCEP defines no hotspot or critical-domain mutational-density rule for this gene.	cspec
PM2	Not met	Not met: gnomAD v4.1 overall frequency 0.03911% (631/1,613,474 alleles) exceeds the 0.001% PM2 threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: the reported breast-cancer and CLL cases are not A-T probands and provide no in-trans pathogenic allele evidence.	cspec vcep_atm_pm3_bp2_1_5 PMID:17393301 PMID:24172824
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, and this is an internal missense substitution.	cspec
PM5	N/A	Not applicable: the VCEP's PM5 rule covers only truncating variants, and this missense variant is not eligible.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP designates PM6 as not applicable, and no assumed de novo event is documented.	cspec
PP1	Not assessed	Not assessed: the breast-cancer and CLL reports contain no variant-specific family segregation evidence.	cspec PMID:17393301 PMID:24172824
PP2	N/A	Not applicable: the ATM VCEP designates PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: REVEL 0.733 falls just below the 0.7333 PP3 missense threshold.	cspec revel spliceai PMID:19781682 PMID:24172824
PP4	N/A	Not applicable: the ATM VCEP designates PP4 as not applicable for this gene.	cspec
PP5	Not met	Not met: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this variant.	clinvar
BA1	Not met	Not met: grpmax FAF 0.047375% is below the 0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: grpmax FAF 0.047375% is just below the 0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP designates BS2 as not applicable for this gene.	cspec
BS3	Not assessed	Not assessed: no VCEP-approved functional assay or rescue data for this variant was available.
BS4	N/A	Not applicable: the ATM VCEP designates BS4 as not applicable, and no variant-specific non-segregation evidence is documented.	cspec
BP1	N/A	Not applicable: the ATM VCEP designates BP1 as not applicable for this gene.	cspec
BP2	Not assessed	Not assessed: no unaffected carrier with a pathogenic ATM variant in trans was documented.	cspec vcep_atm_pm3_bp2_1_5 PMID:17393301 PMID:24172824
BP3	N/A	Not applicable: the ATM VCEP designates BP3 as not applicable; this is a missense change, not an in-frame repeat-region indel.	cspec
BP4	Not met	Not met: REVEL 0.733 falls in the 0.249-0.7333 gray zone, above the 0.249 BP4 benign cutoff.	cspec revel spliceai
BP5	N/A	Not applicable: the ATM VCEP designates BP5 as not applicable for this gene.	cspec
BP6	Not met	Not met: no ClinVar expert-panel benign or likely benign assertion exists for this variant.	clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous and deep intronic variants; this is a missense change.	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.