Variant classification summary

NM_000051.3:c.7527G>A

ATM · NP_000042.3:p.(Met2509Ile) · NM_000051.3

GRCh37: chr11:108202182 G>A · GRCh38: chr11:108331455 G>A

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.(Met2509Ile)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.3:c.7527G>A (Met2509Ile) is a missense variant in ATM exon 51. It is absent from gnomAD v4.1 population databases (PM2_Supporting).

2

Multiple in silico computational tools predict a benign effect: REVEL score 0.184 (BP4 threshold ≤0.249); SpliceAI max delta 0.06 (no predicted splicing impact); BayesDel score -0.366 (BP4_Supporting).

3

The variant is classified as 'Non-functional' by computational meta-prediction in Suppl_TableS1 (PMID 40580951, combined score -1.87, medium-high confidence), but this is a computational prediction rather than experimental functional data and does not meet VCEP requirements for PS3 or BS3.

4

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories and as Likely benign by one clinical laboratory (ClinVar Variation ID: 407522). Under VCEP v1.5, PP5 and BP6 are not applicable.

5

No variant-specific literature was identified; seven ClinVar-associated PMIDs were reviewed and none mentioned NM_000051.3:c.7527G>A.

6

Applying ATM VCEP v1.5 rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) result in a classification of Uncertain Significance per Rule 31 (conflicting evidence: ≥1 benign supporting + ≥1 pathogenic supporting).

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	Not met	NM_000051.3:c.7527G>A is a missense variant (Met2509Ile) and does not meet PVS1 null-variant criteria under the ATM VCEP v1.5. PVS1 is applicable only to nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, or exon deletion variants.	vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant resulting in the same amino acid change (Met2509Ile) via a different nucleotide substitution has been identified. Alternate nucleotide changes at c.7527 (c.7527G>T and c.7527G>C) are also not classified as pathogenic in ClinVar.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951 clinvar
PS2	N/A	ATM VCEP v1.5 specifies: do not use for AD or AR disease as informative de novo occurrences have not yet been observed.	cspec
PS3	Not met	No variant-specific experimental functional data is available for NM_000051.3:c.7527G>A. The variant is computationally classified as 'Non-functional' in Suppl_TableS1 (PMID 40580951, combined score -1.87, medium-high confidence), but this is a computational prediction, not experimental rescue assay data. ATM VCEP v1.5 requires experimental functional evidence (failure to rescue ATM-specific phosphorylation targets ± radiosensitivity in ATM-null cells) for PS3 application.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	No case-control studies with statistical significance have been reported for this variant. ATM VCEP v1.5 requires case-control studies demonstrating p-value ≤0.05 and OR/RR ≥2 or lower 95% CI ≥1.5.	cspec
PS5	N/A	PS5 is not defined in the ATM VCEP v1.5 specifications (ClinGen HBOP). The criterion is not part of the current VCEP framework for ATM.	cspec
PM1	N/A	ATM VCEP v1.5 specifies: do not use. 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	NM_000051.3:c.7527G>A is absent from gnomAD v4.1 (allele frequency = 0). This meets the ATM VCEP v1.5 threshold for PM2_Supporting (frequency ≤0.001% in gnomAD v4).	gnomad_v4 cspec
PM5	N/A	ATM VCEP v1.5 specifies PM5_Supporting applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with PTC upstream of p.Arg3047. This variant is a missense substitution (Met2509Ile); PM5 does not apply.	cspec pm5_candidates
PM6	N/A	ATM VCEP v1.5 specifies: do not use 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
PP1	Not met	No segregation data is available for this variant. ATM VCEP v1.5 applies PP1 for autosomal recessive conditions only, requiring co-segregation in affected relatives with both variants identified. For AD conditions, PP1 is not used due to low penetrance.	cspec
PP2	N/A	ATM VCEP v1.5 specifies: do not use. ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	REVEL score of 0.184 does not exceed the ATM VCEP v1.5 threshold of >0.7333 for missense variants. SpliceAI max delta score of 0.06 does not exceed the threshold of ≥0.2 for splicing variants.	revel spliceai cspec
PP4	N/A	ATM VCEP v1.5 specifies: do not use. For AD: breast cancer has multiple genetic etiologies with no distinguishing features. For AR: such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	ATM VCEP v1.5 specifies: Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	NM_000051.3:c.7527G>A is absent from gnomAD v4.1. The ATM VCEP v1.5 BA1 threshold of Grpmax Filtering AF >0.5% is not met.	gnomad_v4 cspec
BS1	Not met	NM_000051.3:c.7527G>A is absent from gnomAD v4.1. The ATM VCEP v1.5 BS1 threshold of Grpmax Filtering AF >0.05% is not met.	gnomad_v4 cspec
BS2	N/A	ATM VCEP v1.5 specifies: do not use. ATM has incomplete penetrance.	cspec
BS3	Not met	No experimental functional data demonstrating that this variant rescues ATM function (kinase activity or radiosensitivity) in ATM-null cells is available. The computational classification as 'Non-functional' from Suppl_TableS1 is a prediction, not experimental rescue assay data. ATM VCEP v1.5 requires experimental evidence of functional rescue for BS3 application.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	ATM VCEP v1.5 specifies: do not use. For AD: co-segregation analysis in low-penetrance genes can yield false positives. For AR: informative instances of lack of co-segregation in A-T families are too rare.	cspec
BP1	N/A	ATM VCEP v1.5 specifies: do not use. Missense pathogenic variants are known for ATM.	cspec
BP2	Not met	No co-occurrence data (homozygous or in trans with a pathogenic ATM variant in unaffected individuals) is available for this variant. ATM VCEP v1.5 BP2 scoring requires proband-level data per the PM3/BP2 table.	vcep_atm_pm3_bp2_1_5
BP4	Met	REVEL score of 0.184 is ≤0.249, meeting the ATM VCEP v1.5 BP4 threshold for missense variants. SpliceAI max delta score of 0.06 is ≤0.1, indicating no predicted splicing impact. BayesDel score of -0.366 is consistent with a benign in silico prediction.	revel spliceai bayesdel cspec
BP5	N/A	ATM VCEP v1.5 specifies: do not use. 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 specifies: Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is applicable to synonymous and deep intronic variants only under ATM VCEP v1.5. NM_000051.3:c.7527G>A is a missense variant (Met2509Ile).	cspec

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