Variant classification summary

NM_000051.4:c.3080A>G

ATM · NP_000042.3:p.(His1027Arg) · NM_000051.4

GRCh37: chr11:108143261 A>G · GRCh38: chr11:108272534 A>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(His1027Arg)

gnomAD AF

6.208511621092053e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is extremely rare in population databases - gnomAD v4.1 total allele frequency 0.00062% and grpmax FAF 0.00036%, both at or below the 0.001% supporting threshold, with no homozygotes.

2

With PM2 (Supporting) as the only met criterion, no Pathogenic, Likely Pathogenic, Benign, Likely Benign, or conflicting-evidence rule is triggered, so the variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Under the ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985) criteria-combination ruleset, a non-VUS call requires at least one of: PVS1 plus (>=1 PS or >=2 PM or 1 PM + 1 PP or >=2 PP); >=2 PS; 1 PS + (>=3 PM or 2 PM + 2 PP or 1 PM + 4 PP); 1 PVS1 + 1 PM; 1 PS + (1 PM or 2 PP); >=3 PM; 2 PM + 2 PP; 1 PM + 4 PP; 1 PVS1 (or PM3_Very Strong) + 1 supporting criterion (VCEP Rule19); 2 BS; BA1; 1 BS + 1 BP; or 2 BP; with only PM2 supporting met, no rule matched and the variant is classified 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	PVS1 applies only to null variants (nonsense, frameshift, canonical splice-site, initiation-codon, and single/multi-exon deletion variants). This variant is a missense change (p.His1027Arg) with no predicted splicing impact (SpliceAI max delta score 0.05), so it cannot trigger PVS1; it would only be reconsidered if RNA evidence demonstrated an out-of-frame splicing consequence, for which none exists.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not met	PS1 requires the same amino acid change to have been established as pathogenic (or likely pathogenic) in another variant. No such comparator exists: the only ClinVar record for a change at codon 1027 is this exact variant itself, classified Uncertain significance by 9 clinical laboratories with no expert-panel submissions, so PS1 is not met.	clinvar pm5_candidates cspec vcep_atm_ps1_1_5 spliceai PMID:25741868
PS2	N/A	PS2 is not applicable under the ATM specification: informative de novo occurrences have not been observed, and de novo evidence is not informative for autosomal recessive ataxia-telangiectasia. No parental testing or de novo occurrence data are available in any case.	cspec
PS3	Not assessed	PS3 can only be applied through functional assays approved by the ATM expert panel (three kinase-activity assays and one radiosensitivity assay). No variant-level result from an approved assay exists for this variant - the only functional-source entry (Sun et al. 2025) is a computational model prediction, not a direct measurement - so insufficient evidence was available and PS3 was not assessed.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control or cohort enrichment data exist for this variant. The available ATM case-control study covered only protein-truncating variants, and the reviewed case series do not report this variant, so PS4 is not met.	PMID:28779002 PMID:25186627 PMID:32885271
PM1	N/A	PM1 is not applicable because the ATM expert panel provides no hotspot- or domain-based PM1 rule for this gene. Consistently, residue 1027 is not a statistically significant hotspot (CancerHotspots) and no curated variant-specific functional evidence exists for p.His1027Arg.	cspec vcep_atm_pvs1_1_5
PM2	Met	PM2 (Supporting) is met: the variant is extremely rare. gnomAD v4.1 total allele frequency is 0.00062% (10/1,610,692 alleles, no homozygotes) with a grpmax filtering allele frequency of 0.00036%, both at or below the specification's 0.001% threshold; rarity is corroborated by gnomAD v2.1 (0.00040%) and absence from gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Not assessed	PM3 requires observations of the variant in ataxia-telangiectasia probands carrying a second ATM variant. No such observation exists - none of the reviewed publications mention this variant, all 9 ClinVar submissions are Uncertain significance with no phase or zygosity detail, and no homozygotes are reported - so insufficient evidence was available and PM3 was not assessed.	vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4
PM4	N/A	PM4 is restricted to stop-loss variants under the ATM specification. This is a missense substitution that changes a single amino acid without altering protein length or disrupting the stop codon, so PM4 does not apply.	cspec
PM5	N/A	PM5 is not applicable under the ATM specification, which limits the rule to truncating and splice variants with premature termination codons upstream of p.Arg3047; a missense variant is outside that scope. Even under the classic reading, no other pathogenic missense at residue 1027 is documented (ClinVar lists only this variant, as Uncertain significance), so the outcome is unchanged.	cspec pm5_candidates clinvar
PM6	N/A	PM6 is not applicable under the ATM specification: assumed-de-novo evidence is not weighted in autosomal recessive disease. No assumed de novo occurrence or parental testing data exist.	cspec
PP1	Not assessed	PP1 requires segregation of the variant in affected relatives, with both variants identified in the proband. No segregation data exist for this variant (no affected relatives tested, no meiosis or parental genotype information), so insufficient evidence was available and PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable because the ATM specification does not evaluate the gene under the missense-mechanism premise of PP2: ATM-associated disease is driven predominantly by loss of function.	cspec pvs1_gene_context
PP3	Not met	PP3 is not met on either computational path calibrated by the ATM specification: REVEL is 0.349, well below the >0.7333 pathogenic threshold, and SpliceAI max delta is 0.05, below the >=0.2 threshold. Secondary predictors (BayesDel, AlphaMissense, EVE, CADD) also do not indicate a damaging effect.	revel spliceai cspec vcep_suppl_tables1_pmid_40580951 bayesdel
PP4	N/A	PP4 is not applicable because the ATM specification does not use phenotype specificity as an independent criterion; for this recessive condition, phenotype specificity is captured through the PM3 framework.	cspec
PP5	N/A	PP5 is not applicable because there is no expert-panel classification of Pathogenic or Likely pathogenic for this variant: ClinVar lists it as Uncertain significance from 9 ordinary clinical laboratory submissions, with no expert panel input.	clinvar cspec
BA1	Not met	BA1 is not met: it requires a grpmax filtering allele frequency above 0.5%, and the observed grpmax FAF is 0.00036% - more than a thousand-fold below the threshold, with no homozygotes and no ancestry-specific enrichment.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS1	Not met	BS1 is not met: it requires a grpmax filtering allele frequency above 0.05%, and the observed grpmax FAF of 0.00036% is roughly 140-fold lower. No homozygotes are observed in any dataset and the variant is absent from gnomAD-Canada, consistent with a rare variant rather than a common benign polymorphism.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS2	N/A	BS2 is not applicable: the ATM expert panel specification explicitly marks it as not applicable, and the gene-specific specification takes precedence over the generic ACMG/AMP framework.	cspec
BS3	Not assessed	BS3 requires demonstration that the variant does not damage ATM function in a panel-approved assay. No approved-assay result exists for this variant - the only functional-source entry (Sun et al. 2025) is a computational model prediction, not a direct measurement - so insufficient evidence was available and BS3 was not assessed.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	BS4 is not applicable under the ATM specification: informative instances of lack of co-segregation in A-T families are considered too rare to be weighted, and no lack-of-segregation data exist.	cspec
BP1	N/A	BP1 is not applicable because loss of function is an established disease mechanism for ATM, which is the opposite of the premise BP1 requires. Independently, this is a missense variant, not a truncating one.	cspec pvs1_gene_context
BP2	Not assessed	BP2 requires observations of unaffected carriers who carry this variant in trans with a pathogenic ATM variant (or evidence of a cis configuration). No such observations exist - no submission or publication reports this variant alongside a pathogenic allele, and population-database carrier alleles carry no phase information - so insufficient evidence was available and BP2 was not assessed.	vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions; this is a missense single-nucleotide change, and the ATM specification explicitly disallows BP3, so it is not applicable.	cspec
BP4	Not met	BP4 is not met: under the rule as applied, missense variants are evaluated only on the REVEL threshold (<= 0.249), and REVEL is 0.349 - above the threshold and inside the specification's gray zone. Although the SpliceAI score is low, the splicing sub-path does not apply to missense variants because it only rules out one damaging mechanism, so BP4 remains not met.	revel spliceai cspec vcep_suppl_tables1_pmid_40580951 bayesdel
BP5	N/A	BP5 is not applicable under the ATM specification, and no alternate molecular basis of disease is documented for a proband carrying this variant.	cspec
BP6	N/A	BP6 is not applicable because there is no expert-panel classification of Benign or Likely benign for this variant: ClinVar lists it as Uncertain significance from 9 ordinary clinical laboratory submissions.	clinvar cspec
BP7	N/A	BP7 applies to synonymous and deep intronic variants; this is a missense change (p.His1027Arg, exon 21), so it falls outside the criterion's scope.	cspec

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