Variant classification summary

NM_000051.4:c.2689T>A

ATM · NP_000042.3:p.(Phe897Ile) · NM_000051.4

GRCh37: chr11:108139187 T>A · GRCh38: chr11:108268460 T>A

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Phe897Ile)

gnomAD AF

3.531734180619082e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.2689T>A (p.Phe897Ile) in ATM is classified as Likely Benign based on two benign supporting criteria: BS3_Supporting (functional assay data demonstrates retained ATM kinase activity) and BP4_Supporting (REVEL 0.069, SpliceAI max delta 0.02, and six in silico predictors show no deleterious effect).

2

No pathogenic criteria were met. The variant is present in gnomAD v4 at low frequency (AF 3.53×10⁻⁵, 57/1,613,938 alleles) but does not meet PM2_Supporting (threshold ≤0.001%). It has been reported in ClinVar as Uncertain Significance (Variation ID 188232, 16 clinical laboratories).

3

The variant was observed in one ovarian cancer proband (PMID 29371908) but no segregation data are available. It has been reported in COSMIC (COSV99069668, n=3 somatic observations) but without established oncogenic significance.

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	Missense substitution (Phe897Ile); PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites) per VCEP HBOP ATM PVS1 decision tree.
PS1	Not met	No pathogenic or likely pathogenic missense variant identified at residue Phe897 to serve as a PS1 comparator. Other substitutions at this position (F897V, F897L, F897Y, F897S, F897C) are classified as VUS or are of uncertain significance in ClinVar and VCEP functional data.	vcep_suppl_tables1_pmid_40580951 clinvar
PS2	N/A	VCEP HBOP panel explicitly marks PS2 as Not Applicable for ATM.
PS3	Not met	Functional assay data from the VCEP supplementary table (PMID 40580951) classifies F897I as 'Functional' with 'Medium-high' confidence, indicating retention of ATM kinase activity. The variant does not demonstrate loss of function; PS3 is not met.	vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control study meeting VCEP PS4 thresholds (p≤0.05 AND OR≥2 or lower 95% CI≥1.5) identified for this variant. The variant is rare in population databases (gnomAD v4 AF 3.53×10⁻⁵) but no enrichment in affected cohorts has been demonstrated.	gnomad_v4 gnomad_v2
PS5	Not assessed	No additional source of pathogenic evidence identified beyond what was evaluated under other criteria. No new strong functional or clinical data available.
PM1	N/A	VCEP HBOP panel explicitly marks PM1 as Not Applicable for ATM.
PM2	Not met	gnomAD v4 allele frequency is 3.53×10⁻⁵ (0.00353%; 57/1,613,938 alleles), exceeding the VCEP PM2_Supporting threshold of ≤0.001%. Observed in 54 alleles in the European (non-Finnish) subpopulation; not a singleton observation.	gnomad_v4
PM3	N/A	Skipped: PM3 (in trans with pathogenic variant for recessive disorders) requires observation of the variant in trans with a pathogenic ATM variant in an A-T-affected proband; no such data were collected for this case.
PM4	N/A	Skipped: PM4 (protein length change) applies to stop-loss or in-frame deletion/insertion variants; this is a missense substitution.
PM5	N/A	PM5 per VCEP HBOP applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with NMD-prone PTCs. This is a missense substitution (Phe897Ile).
PM6	N/A	VCEP HBOP panel explicitly marks PM6 as Not Applicable for ATM.
PP1	Not met	No segregation data available. The variant was observed in a single proband with ovarian cancer diagnosed at age 67 (PMID 29371908, patient 17,161, from a BRCA2 c.5217_5223delTTTAAGT family) but no co-segregation analysis in relatives was performed.	PMID:29371908
PP2	N/A	VCEP HBOP panel explicitly marks PP2 as Not Applicable for ATM.
PP3	Not met	REVEL score 0.069 falls below the VCEP PP3 missense threshold of >0.7333. SpliceAI max delta score 0.02 is below the VCEP PP3 splicing threshold of ≥0.2. No computational evidence supports a deleterious effect.	revel spliceai bayesdel
PP4	N/A	VCEP HBOP panel explicitly marks PP4 as Not Applicable for ATM.
PP5	N/A	VCEP HBOP panel explicitly marks PP5 as Not Applicable for ATM.
BA1	Not met	gnomAD v4 grpmax filtering allele frequency is 3.59×10⁻⁵ (0.00359%), well below the VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Not met	gnomAD v4 grpmax filtering allele frequency is 3.59×10⁻⁵ (0.00359%), below the VCEP BS1 threshold of >0.05%.	gnomad_v4
BS2	N/A	VCEP HBOP panel explicitly marks BS2 as Not Applicable for ATM.
BS3	Met	Functional assay data from the VCEP supplementary table (PMID 40580951) classifies F897I as 'Functional' with 'Medium-high' confidence, indicating retained ATM kinase activity. Per VCEP HBOP BS3 rules, rescue of an ATM-specific feature (kinase activity) supports BS3_Supporting.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	VCEP HBOP panel explicitly marks BS4 as Not Applicable for ATM.
BP1	N/A	VCEP HBOP panel explicitly marks BP1 as Not Applicable for ATM.
BP2	Not met	No co-occurrence data in trans with a pathogenic ATM variant in Ataxia Telangiectasia probands is available. The variant has not been observed in homozygous state in population databases (gnomAD homozygotes = 0).	gnomad_v4 gnomad_v2
BP3	N/A	Skipped: BP3 (in-frame deletions/insertions in repetitive regions) applies to in-frame indels in repetitive regions without known function; this is a missense substitution.
BP4	Met	REVEL score 0.069 is ≤0.249 (VCEP BP4 missense threshold). SpliceAI max delta score 0.02 is ≤0.1 (VCEP BP4 splicing threshold). Additionally, six in silico protein prediction tools showed no deleterious effect for this variant (PMID 29371908, Fig. 2).	revel spliceai bayesdel PMID:29371908
BP5	N/A	VCEP HBOP panel explicitly marks BP5 as Not Applicable for ATM.
BP6	N/A	VCEP HBOP panel explicitly marks BP6 as Not Applicable for ATM.
BP7	N/A	BP7 per VCEP applies to synonymous and deep intronic variants. This is a missense substitution (Phe897Ile). BP7(RNA) also applies only to silent substitutions and intronic variants.

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