Variant classification summary

NM_000051.4:c.6572+11C>T

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108192158 C>T · GRCh38: chr11:108321431 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

8.17965496728138e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.6572+11C>T is an intronic variant located at position +11 in intron 45 of ATM, outside the canonical splice donor site. SpliceAI predicts no splicing impact (max delta score = 0.00), satisfying BP4 (supporting). The variant position at +11 is further than +7 from the donor site, meeting the ATM VCEP definition of a deep intronic variant for BP7 (supporting).

2

This variant is present in gnomAD v4.1 at an allele frequency of 0.00818% (132/1,613,760 alleles; grpmax FAF = 0.0102%) and in gnomAD v2.1 at 0.00495% (14/282,814 alleles). The frequency exceeds the VCEP PM2_Supporting threshold of ≤0.001% but does not reach BS1 (>0.05%) or BA1 (>0.5%) thresholds.

3

This variant has been reported in ClinVar as Likely benign by four clinical laboratories and as Benign by one clinical laboratory (ClinVar Variation ID: 490663). While ClinVar consensus favors a benign interpretation, the ATM VCEP does not permit use of BP6, and this evidence is noted for context only.

4

No functional studies, case-control data, segregation data, or de novo observations were identified for this variant. PVS1 is not applicable as the variant lies outside the canonical ±1,2 splice sites. PS1 cannot be applied without a PP3 baseline (SpliceAI <0.2).

5

Applying the ATM VCEP v1.5.0 ACMG/AMP combination rules: BP4_Supporting and BP7_Supporting are both met (2 benign supporting criteria). Rule 19 (≥2 Benign Supporting) yields a classification of Likely Benign.

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	Not met	NM_000051.4:c.6572+11C>T is an intronic variant at position +11, outside the canonical ±1,2 splice donor/acceptor dinucleotides. SpliceAI predicts no splicing impact (max delta = 0.00). The ATM VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites); this variant does not qualify.	spliceai vcep_atm_pvs1_1_5
PS1	Not met	The ATM PS1 splicing table requires a PP3 baseline (SpliceAI ≥0.2) for variants located outside donor/acceptor ±1,2 positions. SpliceAI max delta for this variant is 0.00, which does not meet PP3. Without a PP3 baseline, PS1 cannot be applied per the VCEP PS1 splicing framework. No known pathogenic variant at this nucleotide position with a matching predicted splicing event was identified.	spliceai vcep_atm_ps1_1_5
PS2	N/A	ATM VCEP specifies PS2 as not applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not assessed	No functional studies evaluating ATM kinase activity or radiosensitivity rescue for NM_000051.4:c.6572+11C>T were identified. The ATM VCEP PS3 framework requires demonstration that the variant fails to rescue ATM-specific features and/or radiosensitivity.
PS4	Not assessed	No case-control studies with adequate statistical power were identified for NM_000051.4:c.6572+11C>T. The ATM VCEP PS4_Strong requires case-control data with p≤0.05 and OR≥2 or lower 95% CI ≥1.5. Proband counting (PS4_Moderate) is explicitly excluded by the VCEP.
PS5	N/A	PS5 is not included in the ATM VCEP v1.5.0 criteria framework.	cspec
PM1	N/A	ATM VCEP specifies PM1 as not applicable: benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined.	cspec
PM2	Not met	The ATM VCEP PM2_Supporting threshold is ≤0.001% (≤0.00001) in gnomAD v4. This variant has an allele frequency of 0.00818% (132/1,613,760 alleles) in gnomAD v4.1, which exceeds the VCEP PM2 threshold.	gnomad_v4
PM5	N/A	ATM VCEP PM5_Supporting applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied based on observed splicing impact. This is an intronic variant at +11 with no predicted splicing impact (SpliceAI max delta = 0.00). Neither condition is met.	spliceai cspec
PM6	N/A	ATM VCEP specifies PM6 as not applicable for both AD and AR disease: informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	No segregation data in affected relatives was identified for NM_000051.4:c.6572+11C>T. The ATM VCEP PP1 framework applies to autosomal recessive conditions (A-T) and requires observation in affected relatives.
PP2	N/A	ATM VCEP specifies PP2 as not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	The ATM VCEP PP3 threshold for splicing prediction is SpliceAI ≥0.2 for intronic variants outside donor/acceptor ±1,2 sites. SpliceAI max delta for this variant is 0.00, which does not meet the threshold. REVEL is not applicable as this is not a missense variant.	spliceai
PP4	N/A	ATM VCEP specifies PP4 as not applicable for both AD and AR disease: breast cancer has multiple genetic etiologies (genetic heterogeneity), and A-T evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	ATM VCEP specifies PP5 as not applicable.	cspec
BA1	Not met	The ATM VCEP BA1 (Stand Alone) threshold is grpmax filtering AF >0.5% in gnomAD v4. The grpmax FAF for this variant is 0.0102%, far below the BA1 threshold.	gnomad_v4
BS1	Not met	The ATM VCEP BS1 (Benign Strong) threshold is grpmax filtering AF >0.05% in gnomAD v4. The grpmax FAF for this variant is 0.0102%, which does not meet the BS1 threshold.	gnomad_v4
BS2	N/A	ATM VCEP specifies BS2 as not applicable.	cspec
BS3	Not assessed	No functional studies demonstrating rescue of ATM-specific features and/or radiosensitivity were identified for NM_000051.4:c.6572+11C>T. The ATM VCEP BS3 framework requires functional assay evidence.
BS4	N/A	ATM VCEP specifies BS4 as not applicable.	cspec
BP1	N/A	ATM VCEP specifies BP1 as not applicable.	cspec
BP2	Not assessed	No proband data for unaffected individuals (≥18 years, no A-T) with this variant observed in trans or homozygous with a pathogenic/likely pathogenic ATM variant was identified. Assessment requires case-level data per the ATM PM3/BP2 point table.
BP4	Met	SpliceAI predicts no splicing impact for this intronic variant (max delta = 0.00). This meets the ATM VCEP BP4_Supporting threshold for splicing (SpliceAI ≤0.1).	spliceai
BP5	N/A	ATM VCEP specifies BP5 as not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance.	cspec
BP6	N/A	ATM VCEP specifies BP6 as not applicable for this VCEP, per ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	Met	NM_000051.4:c.6572+11C>T is an intronic variant at position +11, which is further than +7 from the donor site. The ATM VCEP BP7 rule applies to deep intronic variants defined as further than (but not including) +7 at donor sites. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a lack of aberrant splicing.	spliceai cspec
BP3	N/A	ATM VCEP specifies BP3 as not applicable.	cspec
PM3	N/A	PM3 requires observation in trans with a pathogenic variant in A-T probands. No proband-level phase data was provided for NM_000051.4:c.6572+11C>T.	cspec
PM4	N/A	ATM VCEP specifies PM4 for stop-loss variants only. NM_000051.4:c.6572+11C>T is an intronic substitution, not a stop-loss variant.	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.