NM_000051.3:c.4110_4111delinsAA

ATM · NP_000042.3:p.(Asp1371Asn) · NM_000051.3

GRCh37: chr11:108159704 GG>AA · GRCh38: chr11:108288977 GG>AA

Gene: ATM Transcript: NM_000051.3

Final call

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Asp1371Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting under the ATM VCEP v1.5 threshold of ≤0.001%.

SpliceAI predicts no splice impact (max delta 0.01), meeting BP4_Supporting under the ATM VCEP v1.5 splicing threshold of ≤0.1. REVEL is unavailable for this indel variant.

The same amino acid change p.(Asp1371Asn) exists via c.4111G>A, classified as Uncertain Significance in ClinVar. The VCEP functional supplement (Suppl_TableS1, PMID 40580951) computationally predicts the D1371N change as 'Functional' via DeepATM, but this does not constitute experimental functional evidence for PS3 or BS3.

One pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) are met. Per ACMG/AMP 2015 combination rules (Rule31), >=1 benign supporting and >=1 pathogenic supporting results in Uncertain Significance with conflicting evidence.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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	This is an in-frame 2-bp deletion-insertion (c.4110_4111delinsAA) producing a missense change (p.Asp1371Asn), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 under the ATM VCEP v1.5 applies only to null variants.	vcep_atm_pvs1_1_5 cspec
PS1	Not met	The same amino acid change p.(Asp1371Asn) exists via c.4111G>A (a single-nucleotide missense variant), but this comparator is classified as Uncertain Significance in ClinVar, not Pathogenic or Likely Pathogenic. PS1 requires a previously established pathogenic variant with the same amino acid change. SpliceAI confirms no cryptic splice impact for the variant under assessment (max delta 0.01).	cspec spliceai vcep_suppl_tables1_pmid_40580951
PS2	N/A	VCEP ATM v1.5: de novo occurrences have not yet been observed for ATM; PS2 is not applicable for autosomal dominant or autosomal recessive ATM-related disease.	cspec
PS3	Not met	No experimental functional data (rescue assays for ATM-specific phosphorylation or radiosensitivity) has been identified for this variant or for the same amino acid change D1371N. The VCEP Suppl_TableS1 (PMID 40580951) includes a computational DeepATM prediction for c.4111G>A (D1371N) classified as 'Functional', but this is a predictive score, not experimental functional evidence meeting PS3 requirements.	cspec vcep_suppl_tables1_pmid_40580951 oncokb
PS4	Not met	No case-control studies have been reported for this variant. PS4 requires a statistically significant enrichment in affected individuals versus controls (p≤0.05, OR≥2 or lower 95% CI≥1.5).	cspec
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria framework and is not listed in the ATM VCEP v1.5 specifications.
PM1	N/A	VCEP ATM v1.5: PM1 is not applicable. Benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined for ATM.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting threshold of allele frequency ≤0.001% in gnomAD v4.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	N/A	VCEP ATM v1.5: PM4 is applicable only for stop-loss variants. In-frame insertions or deletions smaller than a single exon are explicitly excluded. This variant is a 2-bp in-frame delins, not a stop-loss variant.	cspec
PM5	N/A	VCEP ATM v1.5: PM5_Supporting applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied. This is an in-frame missense variant (D1371N) and does not meet PM5 criteria.	cspec pm5_candidates
PM6	N/A	VCEP ATM v1.5: PM6 is not applicable for autosomal dominant or autosomal recessive ATM-related disease. Informative de novo occurrences have not yet been observed.	cspec
PP1	Not met	No co-segregation data is available for this variant. PP1 under the VCEP applies to autosomal recessive (A-T) conditions with segregation in affected relatives, but no family studies have been identified.	cspec
PP2	N/A	VCEP ATM v1.5: PP2 is not applicable. ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	REVEL score is not available for this indel variant (REVEL only scores single-nucleotide missense changes). SpliceAI max delta score is 0.01, well below the VCEP PP3 threshold of ≥0.2 for splicing prediction. Neither the missense (REVEL >0.733) nor the splicing (SpliceAI ≥0.2) rule for PP3 is met.	spliceai cspec
PP4	N/A	VCEP ATM v1.5: PP4 is not applicable. For autosomal dominant breast cancer, genetic heterogeneity precludes use. For autosomal recessive A-T, phenotype evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	VCEP ATM v1.5: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires a Grpmax Filtering AF >0.5%, which is not met.	gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires a Grpmax Filtering AF >0.05%, which is not met.	gnomad_v4 cspec
BS2	N/A	VCEP ATM v1.5: BS2 is not applicable. ATM has incomplete penetrance, and healthy adults may carry pathogenic ATM variants without manifesting disease.	cspec
BS3	Not met	No experimental functional studies demonstrating rescue of ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity have been identified for this variant. The VCEP Suppl_TableS1 DeepATM computational prediction for the same amino acid change D1371N (via c.4111G>A) classifies it as 'Functional' but this is a predictive score, not experimental evidence meeting BS3 requirements.	cspec vcep_suppl_tables1_pmid_40580951
BS4	N/A	VCEP ATM v1.5: BS4 is not applicable. For autosomal dominant conditions, co-segregation analysis in low-penetrance genes can lead to false-positive results. For autosomal recessive A-T, informative instances of lack of co-segregation are too rare to weight.	cspec
BP1	N/A	VCEP ATM v1.5: BP1 is not applicable. Missense pathogenic variants are known for ATM, so a missense variant cannot be discounted on the basis that only truncating variants cause disease.	cspec
BP2	Not met	No data on unaffected individuals carrying this variant in trans with a known pathogenic ATM variant or in homozygous state are available. BP2 requires observation of the variant in an unaffected individual aged ≥18 years with no evidence of A-T, in trans with a pathogenic/likely pathogenic ATM variant.	cspec
BP3	N/A	VCEP ATM v1.5: BP3 is not applicable. The original ACMG description is 'in-frame deletions/insertions in a repetitive region without a known function' but the VCEP does not apply this criterion for ATM.	cspec
BP4	Met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01 ≤ 0.1 threshold), meeting the VCEP BP4 splicing rule. REVEL score is not available for this indel variant, so the missense-specific BP4 rule cannot be assessed. The SpliceAI result confirms no cryptic splice alteration, which is a valid line of benign computational evidence.	spliceai cspec
BP5	N/A	VCEP ATM v1.5: BP5 is not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance for co-occurring variants in the general population.	cspec
BP6	N/A	VCEP ATM v1.5: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	VCEP ATM v1.5: BP7 applies only to synonymous and deep intronic variants. This variant is a missense change (p.Asp1371Asn) arising from an in-frame delins and does not fall within the BP7 scope.	cspec spliceai

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