Variant classification summary

NM_000051.4:c.662+13_662+14delCT

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108114854 ATC>A · GRCh38: chr11:108244127 ATC>A

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

1.2395951482245899e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.662+13_662+14del is an intronic deletion in ATM at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus.

2

SpliceAI predicts no significant splice impact (max delta score=0.05), indicating this variant is unlikely to disrupt normal ATM mRNA splicing.

3

The variant is present at extremely low frequency in gnomAD v4.1 (2/1,613,430 alleles; AF=1.24e-06; 0.000124%), meeting ATM VCEP PM2_Supporting criteria (<=0.001%).

4

The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and absent from ClinVar classifications.

5

As an intronic variant beyond +7 with no predicted splice impact, BP7 (deep intronic, supporting) and BP4 (no predicted splicing impact, supporting) both apply per ATM VCEP v1.5.0.

6

No functional studies (PS3/BS3), segregation data (PP1), case-control studies (PS4), or phase observations (PM3/BP2) are available for this variant.

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.662+13_662+14del is an intronic deletion at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus. Per the ATM VCEP v1.5.0 PVS1 decision tree, PVS1 for intronic variants outside the canonical splice dinucleotide requires a predicted or observed splicing defect. SpliceAI predicts no significant splice impact (max delta score=0.05), falling below the PP3 threshold of >=0.2. No RNA functional data demonstrating aberrant splicing are available. PVS1 is therefore not met.	spliceai pvs1_gene_context pvs1_variant_assessment
PS1	Not met	Per the ATM VCEP v1.5.0 PS1 splicing table, PS1 requires a known pathogenic or likely pathogenic reference variant at the same nucleotide position with similar or stronger computational prediction of the same splicing outcome. No pathogenic/likely pathogenic comparator variant has been identified at c.662+13_662+14 in ClinVar or the VCEP reference datasets. No reference variant is available for PS1 comparison.	cspec
PS2	N/A	ATM VCEP v1.5.0: PS2 is not applicable for AD or AR disease. Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	Per ATM VCEP v1.5.0, PS3 requires functional studies demonstrating a damaging effect on ATM-specific features (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity rescue failure. No functional study assessing this exact variant was identified in the VCEP functional dataset (Suppl_TableS1_PMID_40580951) or in the literature. The variant is an intronic deletion and is not represented in the ATM missense functional catalog.	cspec
PS4	Not met	Per ATM VCEP v1.5.0, PS4_Strong requires case-control studies with p-value <=0.05 and OR/HR/RR >=2 or lower 95% CI >=1.5. No case-control study or proband enrichment data have been published for this variant. The variant is extremely rare (gnomAD v4.1 AF=1.24e-06) and absent from ClinVar submissions with clinical assertions.	cspec gnomad_v4 clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar classifications and no published clinical report asserts pathogenicity.	clinvar
PM1	N/A	ATM VCEP v1.5.0: PM1 is not applicable. Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.	cspec
PM2	Met	Per ATM VCEP v1.5.0, PM2_Supporting applies when frequency is <=0.001% in gnomAD v4. This variant is present at extremely low frequency in gnomAD v4.1 (AF=1.24e-06, 0.000124%, 2/1,613,430 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The frequency is well below the 0.001% threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM4	N/A	ATM VCEP v1.5.0: PM4 is restricted to stop-loss variants only. This is a small intronic deletion and does not meet the VCEP PM4 criteria.	cspec
PM5	N/A	ATM VCEP v1.5.0: PM5_Supporting applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied based on high-quality observed splicing impact and must be NMD-prone. This variant is an intronic deletion with no predicted splice defect (SpliceAI=0.05) and no premature termination codon; PVS1 has not been applied. PM5 is not applicable.	cspec pm5_candidates spliceai
PM6	N/A	ATM VCEP v1.5.0: PM6 is not applicable for AD or AR disease. Informative de novo occurrences have not yet been observed.	cspec
PP1	Not met	Per ATM VCEP v1.5.0, PP1 for autosomal recessive conditions requires co-segregation in affected relatives with both variants identified in the proband. No family-based segregation analysis or linkage data have been published for this variant.	cspec
PP2	N/A	ATM VCEP v1.5.0: PP2 is not applicable. ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	Per ATM VCEP v1.5.0, PP3 for splicing requires SpliceAI >=0.2 for intronic variants outside donor/acceptor +/-1,2 sites. SpliceAI predicts no significant splice impact for this variant (max delta score=0.05), which is below the 0.2 threshold. Additionally, VCEP guidance states PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes. REVEL/BayesDel scores are not applicable to this intronic deletion.	spliceai cspec
PP4	N/A	ATM VCEP v1.5.0: PP4 is not applicable. For autosomal dominant disease, breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes. For autosomal recessive disease, such evidence is built into the Ataxia Telangiectasia PM3/BP2 table.	cspec
PP5	N/A	ATM VCEP v1.5.0: PP5 is not applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4. This variant is extremely rare (AF=1.24e-06, 0.000124% in gnomAD v4.1), far below the 0.5% BA1 threshold.	gnomad_v4 cspec
BS1	Not met	Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4. This variant is extremely rare (AF=1.24e-06, 0.000124% in gnomAD v4.1), far below the 0.05% BS1 threshold.	gnomad_v4 cspec
BS2	N/A	ATM VCEP v1.5.0: BS2 is not applicable. ATM has incomplete penetrance.	cspec
BS3	Not met	Per ATM VCEP v1.5.0, BS3 requires functional studies showing rescue of ATM-specific features and/or radiosensitivity. No functional study demonstrating a benign effect (normal splicing, protein expression, or kinase activity) has been identified for this variant. The variant is absent from the VCEP functional dataset (Suppl_TableS1, PMID:40580951).	cspec
BS4	N/A	ATM VCEP v1.5.0: BS4 is not applicable. For autosomal dominant disease, co-segregation analysis in low-penetrance genes can lead to false positive results. For autosomal recessive disease, informative instances of lack of co-segregation in A-T families are too rare.	cspec
BP1	N/A	ATM VCEP v1.5.0: BP1 is not applicable. Missense pathogenic variants are known for ATM.	cspec
BP2	Not met	Per ATM VCEP v1.5.0, BP2 requires observation of the variant in cis with a pathogenic ATM variant, or in trans with a P/LP variant in an unaffected individual aged 18+ without evidence of A-T. No such observation has been reported for this variant in ClinVar or the literature.	cspec clinvar
BP3	N/A	ATM VCEP v1.5.0: BP3 is not applicable; the VCEP instructs not to use this criterion.	cspec
BP4	Met	Per ATM VCEP v1.5.0, BP4 for splicing applies when SpliceAI <=0.1, indicating no predicted impact via splicing. SpliceAI max delta score for this variant is 0.05, which falls below the 0.1 threshold. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing.	spliceai cspec
BP5	N/A	ATM VCEP v1.5.0: BP5 is 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 v1.5.0: BP6 is not applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	Met	Per ATM VCEP v1.5.0, BP7 applies to deep intronic variants defined as further than (but not including) +7 at donor sites. This variant is at position +13/+14 of the intron 6 donor site, which is beyond +7. SpliceAI predicts no significant splice impact (max delta=0.05). No aberrant RNA defect has been observed.	cspec spliceai

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.