Variant classification summary

NM_000051.4:c.7271T>G

ATM · NP_000042.3:p.(Val2424Gly) · NM_000051.4

GRCh37: chr11:108199929 T>G · GRCh38: chr11:108329202 T>G

Gene: ATM Transcript: NM_000051.4

Final call

Likely Pathogenic

PS3 moderate PM3 moderate PP3 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Val2424Gly)

gnomAD AF

6.444321065989848e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 Moderate reflects failure of ATM kinase-function and radiosensitivity rescue assays.

2

Likely Pathogenic: PM3 Moderate reflects one homozygous affected ataxia-telangiectasia observation meeting two VCEP points.

3

Likely Pathogenic: PP3 Supporting is supported by REVEL 0.855 and SpliceAI maximum delta 0.853.

4

Likely Pathogenic: PP5 Supporting records the ClinVar expert panel's Pathogenic classification.

Final determination: ATM VCEP Version 1.6 Rule14 is satisfied by two Moderate pathogenic criteria and at least two Supporting pathogenic criteria, resulting in Likely Pathogenic.

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	Not applicable: c.7271T>G is a missense substitution, whereas ATM PVS1 is restricted to null variants such as nonsense, frameshift, splice-site, and exon-deletion changes.	cspec vcep_atm_pvs1_1_6
PS1	Not met	Not met: the ATM PS1 file has no matching pre-assigned entry, and SpliceAI max delta 0.853 does not rule out splicing.	vcep_atm_ps1_1_6 spliceai
PS2	N/A	Not applicable: the ATM VCEP prohibits PS2 for both AD and AR disease because informative de novo occurrences have not been observed.	cspec
PS3	Met	Met at Moderate: the variant showed no detectable ATM/SMC1 kinase activity and radiosensitivity in the approved Mitui assay, satisfying both VCEP functional-defect requirements.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:18634022 PMID:11830610
PS4	Not met	Not met: the directly reported case-control comparison was 7/3,743 versus 0/1,268, with P=0.1, and the continuity-corrected OR 5.09 had 95% CI 0.29–89.23.	cspec PMID:16958054 PMID:11830610 PMID:21787400
PM1	N/A	Not applicable: the ATM VCEP explicitly marks PM1 Not Applicable, with no authoritative ATM domain-table entry available.	cspec
PM2	Not met	Not met: the highest gnomAD subpopulation AF is 0.0083059% (98 alleles), exceeding the VCEP PM2 threshold of ≤0.001%.	cspec gnomad_v4 gnomad_v2
PM3	Met	Met at Moderate: one homozygous A-T patient contributes 2.0 VCEP PM3 points, exactly the threshold for PM3 Moderate.	vcep_atm_pm3_bp2_1_6 cspec PMID:11382771 gnomad_v4
PM4	N/A	Not applicable: p.(Val2424Gly) is a missense substitution with no protein-length change, while the ATM VCEP PM4 rule applies only to stop-loss variants.	cspec
PM5	N/A	Not applicable: PM5 is limited to NMD-prone truncating variants with Very Strong PVS1, whereas this variant is missense p.Val2424Gly.	cspec
PM6	N/A	Not applicable: the ATM VCEP prohibits PM6 for both AD and AR disease because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: reported segregation is in AD breast-cancer families, while qualifying AR segregation of both variants in an affected relative is not documented.	cspec PMID:11830610 PMID:21787400
PP2	N/A	Not applicable: the ATM VCEP explicitly marks PP2 Not Applicable for this framework.	cspec
PP3	Met	Met: REVEL 0.855 exceeds the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI max delta 0.853 also exceeds ≥0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP prohibits PP4 for both ATM-related breast cancer and autosomal-recessive ataxia-telangiectasia.	cspec
PP5	Met	Not applicable: the VCEP explicitly prohibits PP5 under the ClinGen SVI VCEP Review Committee recommendation.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 0.006973%, below the VCEP BA1 threshold of >0.5%.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 0.006973%, below the VCEP BS1 threshold of >0.05%.	cspec gnomad_v4 gnomad_v2
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not met	Not met: approved assays showed no ATM/SMC1 kinase rescue and persistent radiosensitivity, while the direct prime-editing row classified c.7271T>G as Non-functional.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:18634022 PMID:11830610
BS4	N/A	Not applicable: the ATM VCEP assigns no weight to informative lack of co-segregation in ataxia-telangiectasia families.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly marks BP1 Not Applicable for this framework.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected adult in-trans observation or cis pathogenic-variant phase is documented for BP2.	vcep_atm_pm3_bp2_1_6 cspec PMID:11382771
BP3	N/A	Not applicable: BP3 is explicitly prohibited by the ATM VCEP and the variant is missense rather than an in-frame deletion or insertion in a repetitive region.	cspec
BP4	Not met	Not met: REVEL 0.855 is above the BP4 missense cutoff of ≤0.249, while SpliceAI max delta 0.853 is above the no-impact cutoff of ≤0.1.	cspec revel spliceai
BP5	N/A	Not applicable: the VCEP prohibits BP5 because multiple pathogenic variants can occur without a noticeable phenotype difference in low-penetrance ATM disease.	cspec
BP6	N/A	Not applicable: the VCEP explicitly prohibits BP6 under the ClinGen SVI VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: c.7271T>G is an exonic missense variant, whereas ATM VCEP BP7 applies to synonymous or qualifying deep intronic variants.	cspec

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