Variant classification summary

NM_000051.4:c.6095G>A

ATM · NP_000042.3:p.(Arg2032Lys) · NM_000051.4

GRCh37: chr11:108186638 G>A · GRCh38: chr11:108315911 G>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PS3 supporting PM3 moderate PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2032Lys)

gnomAD AF

8.072237835448052e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong is supported by exon skipping with an out-of-frame premature termination.

2

Pathogenic: PS3 supporting is supported by high-confidence direct prime-editing evidence of a non-functional result.

3

Pathogenic: PM3 moderate is supported by three conservative VCEP PM3 points from affected ataxia-telangiectasia observations.

4

Pathogenic: PP3 supporting is supported by a SpliceAI maximum delta of 0.854.

Final determination: ATM VCEP Version 1.6 Rule4 is satisfied by one Very Strong pathogenic criterion and at least two Supporting pathogenic criteria, producing a Pathogenic classification.

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	Met	Met, very strong: observed 89-nucleotide exon skipping causes a frameshift and termination after four amino acids, consistent with the VCEP's NMD-prone FATKIN splice-defect pathway.	cspec vcep_atm_pvs1_1_6 PMID:10330348 PMID:10980530
PS1	Not met	Not met: observed exon 43 skipping prevents the missense PS1 path, and ATM_PS1_1.6.pdf has no c.6095G>A, p.Arg2032Lys, or p.R2032K entry.	vcep_atm_ps1_1_6 PMID:10980530 PMID:10330348
PS2	N/A	Not applicable: the ATM VCEP directs that PS2 not be used because informative de novo occurrences have not been observed.	cspec
PS3	Met	Met at Supporting: direct prime editing classified ATM c.6095G>A as Non-functional with High confidence and DeepATM_predicted=No.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS4	Not met	Not met: one case and zero controls yielded a two-sided Fisher exact p-value of 0.4663, exceeding the VCEP's ≤0.05 requirement.	cspec PMID:22585167
PM1	N/A	Not applicable: the ATM VCEP explicitly marks PM1 Not Applicable, and no authoritative ATM domain-table entry is present.	cspec
PM2	Not met	Not met: highest gnomAD subpopulation AF is 0.00110463%, exceeding the VCEP's at-or-below-0.001% PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	Met	Met at Moderate: the conservative minimum is 3 PM3 points from affected A-T observations, exceeding the VCEP's 2-point Moderate threshold but not its 4-point Strong threshold.	cspec vcep_atm_pm3_bp2_1_6 gnomad_v2 PMID:10330348 PMID:16266405 PMID:10980530
PM4	N/A	Not applicable: PM4 is restricted by the ATM VCEP to stop-loss variants, whereas c.6095G>A is a missense substitution.	cspec
PM5	N/A	Not applicable: the ATM PM5 rule is limited to qualifying NMD-prone truncating variants, whereas c.6095G>A is missense.	cspec
PM6	N/A	Not applicable: the ATM VCEP directs that PM6 not be used because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: affected carriers are reported, but no available report documents complete biallelic genotypes and segregation of both proband variants in affected relatives.	cspec PMID:10980530 PMID:16266405
PP2	N/A	Not applicable: the ATM VCEP explicitly marks PP2 Not Applicable.	cspec
PP3	Met	Met: SpliceAI max delta 0.854 exceeds the VCEP PP3 threshold of >=0.2, despite REVEL 0.436 being below the missense threshold of >.7333.	cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP excludes PP4 for both ATM-related breast cancer and ataxia-telangiectasia phenotype assessment.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits use of PP5 for this VCEP.	cspec
BA1	Not met	Not met: maximum gnomAD grpmax FAF is 0.002854%, below the VCEP's greater-than-0.5% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum gnomAD grpmax FAF is 0.002854%, below the VCEP's greater-than-0.05% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 as not applicable.	cspec
BS3	Not met	Not met: direct prime editing classified c.6095G>A as Non-functional with High confidence, not as rescuing an ATM-specific feature.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
BS4	N/A	Not applicable: the ATM VCEP states that informative lack-of-segregation instances in ataxia-telangiectasia families are too rare to receive weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly marks BP1 Not Applicable.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected adult observation with documented phase, zygosity, and absence of A-T is available for the VCEP's BP2 point assignment.	cspec vcep_atm_pm3_bp2_1_6 PMID:22585167
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable, and this variant is a missense substitution rather than a qualifying repeat-region in-frame indel.	cspec
BP4	Not met	Not met: REVEL 0.436 exceeds the BP4 missense cutoff of <=.249 and SpliceAI max delta 0.854 exceeds the no-impact cutoff of <=0.1.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP instructs reviewers not to use BP5 because ATM's low penetrance permits frequent co-occurring pathogenic variants.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits use of BP6 for this VCEP.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or qualifying deep intronic variants, whereas c.6095G>A is a missense substitution in exon 41.	cspec

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