NM_000051.4:c.838A>G

ATM · NP_000042.3:p.(Ile280Val) · NM_000051.4

GRCh37: chr11:108115690 A>G · GRCh38: chr11:108244963 A>G

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP4 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ile280Val)

gnomAD AF

1.8596324622401628e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.838A>G (p.Ile280Val) is a missense variant in ATM exon 7.

This variant is present in gnomAD v4.1 at extremely low frequency (AF=0.00019%, 3/1,613,222 alleles; grpmax FAF=5.53e-06), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001%.

In silico predictions are benign: REVEL score of 0.043 meets the ATM VCEP BP4_Supporting threshold of ≤0.249. SpliceAI predicts no splicing impact (max delta=0.01).

Systematic functional characterization in Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10, confidence medium-high), neither clearly abrogating nor clearly retaining ATM function, insufficient to apply PS3 or BS3 under ATM VCEP rules.

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories, ClinVar ID 407462, criteria provided single submitter). No expert panel classification is available.

No pathogenic or likely pathogenic variants at ATM residue Ile280 are reported in ClinVar, and PS1 is not met.

Final determination: Rule31 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 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	Missense variant (c.838A>G, p.Ile280Val); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites) per the ATM VCEP PVS1 decision tree.	vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	Not met	No pathogenic or likely pathogenic variant at ATM residue Ile280 has been identified in ClinVar. The ATM VCEP PS1 rule requires a same amino acid change as a previously established pathogenic variant with splicing ruled out for both alterations.	pm5_candidates vcep_atm_ps1_1_5
PS2	N/A	Not applicable per ATM VCEP; de novo occurrences are not informative for ATM-related autosomal recessive (A-T) or autosomal dominant (cancer predisposition) conditions.
PS3	Not met	The systematic functional characterization in the ATM VCEP-supplied Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10, confidence medium-high), neither clearly abrogating nor clearly retaining ATM function. This does not meet the ATM VCEP PS3 requirement of demonstrated failure to rescue ATM-specific features (supporting) or both ATM-specific features and radiosensitivity (moderate).	vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control study data available for this variant. The ATM VCEP requires case-control studies with p-value ≤0.05 and odds ratio ≥2 or lower 95% CI ≥1.5.
PS5	N/A	PS5 is not included in the ATM VCEP v1.5 specification.
PM1	N/A	Not applicable per ATM VCEP; benign and pathogenic variants occur within the same ATM domains, and germline mutational hotspots are not well defined.
PM2	Met	Present in gnomAD v4.1 at very low frequency (AF=0.00019%, 3/1,613,222 alleles; grpmax FAF=5.53e-06), meeting the ATM VCEP threshold of ≤0.001% for PM2_Supporting. Also present at AF=0.00040% (1/250,510 alleles) in gnomAD v2.1.	gnomad_v2 gnomad_v4
PM5	N/A	Missense variant; the ATM VCEP reserves PM5 for frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, and applicable splice variants.	pm5_candidates
PM6	N/A	Not applicable per ATM VCEP; de novo occurrences are not informative for ATM-related autosomal recessive (A-T) or autosomal dominant (cancer predisposition) conditions.
PP1	Not assessed	No segregation data available for this variant. The ATM VCEP requires segregation in affected relatives for PP1 application (1/2/≥3 relatives for supporting/moderate/strong).
PP2	N/A	Not applicable per ATM VCEP; ATM does not have a defined low rate of missense benign variation.
PP3	Not met	REVEL score of 0.043 does not meet the ATM VCEP threshold of >0.7333 for PP3. SpliceAI max delta score of 0.01 further indicates no predicted splicing impact.	revel spliceai bayesdel
PP4	N/A	Not applicable per ATM VCEP. For autosomal recessive A-T, phenotype specificity is built into the PM3/BP2 framework. For autosomal dominant cancer predisposition, breast cancer has multiple genetic etiologies.
PP5	N/A	Not applicable per ATM VCEP; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar classification is VUS (criteria provided, single submitter), which does not meet the PP5 override threshold of 3-star expert panel classification.	clinvar
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency of 5.53e-06 does not meet the ATM VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency of 5.53e-06 does not meet the ATM VCEP BS1 threshold of >0.05%.	gnomad_v4
BS2	N/A	Not applicable per ATM VCEP; healthy adult with full penetrance expected is not defined for ATM-related conditions in the VCEP specification.
BS3	Not met	The systematic functional characterization in the ATM VCEP-supplied Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10), not 'Functional.' This does not meet the ATM VCEP BS3 requirement of demonstrated rescue of ATM-specific features (supporting) or both ATM-specific features and radiosensitivity (moderate).	vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable per ATM VCEP.
BP1	N/A	Not applicable per ATM VCEP; this criterion addresses missense variants in genes where truncating variants cause disease, which does not apply per the ATM VCEP specification.
BP2	Not assessed	No evidence of co-occurrence in trans with a pathogenic variant in unaffected individuals available for BP2 assessment. The ATM VCEP requires proband-level data and confident phenotyping per the PM3/BP2 scoring table.
BP4	Met	REVEL score of 0.043 meets the ATM VCEP threshold of ≤0.249 for BP4 (Supporting). SpliceAI max delta score of 0.01 further indicates no predicted splicing impact. BayesDel score of -0.435 is also consistent with a benign in silico prediction.	revel spliceai bayesdel
BP5	N/A	Not applicable per ATM VCEP; cases with multiple pathogenic variants have been observed in ATM without noticeable phenotypic difference, and ATM has low penetrance.
BP6	N/A	Not applicable per ATM VCEP; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar classification is VUS (criteria provided, single submitter), which does not meet the BP6 override threshold of 3-star expert panel benign classification.	clinvar
BP7	N/A	Missense variant (c.838A>G, p.Ile280Val); BP7 applies only to synonymous and deep intronic variants per the ATM VCEP specification.
BP3	N/A	Missense substitution variant; BP3 applies to in-frame deletions/insertions in a repetitive region without known function.
PM3	N/A	No in-trans co-occurrence data with a pathogenic ATM variant is available for this case.
PM4	N/A	Missense substitution variant; PM4 applies to stop-loss variants per the ATM VCEP specification.

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