Variant classification summary

NM_000051.4:c.1261T>A

ATM · NP_000042.3:p.(Ser421Thr) · NM_000051.4

GRCh37: chr11:108121453 T>A · GRCh38: chr11:108250726 T>A

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ser421Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

For the requested consequence/LOF criteria, the ATM VCEP makes PVS1 inapplicable to this missense variant, PM4 applicable only to stop-loss variants, and BP3 not applicable.

2

PS2, PM6, and BS4 are explicitly Not Applicable in the ATM VCEP v1.6 CSPEC. PP1 is not assessed because no qualifying affected-relative segregation or family testing data are documented.

3

Within this requested group, PS4 is not assessed because the required case-control statistics are unavailable; PP4, PP5, BP5, and BP6 are not applicable under the ATM VCEP.

4

No publications were reviewed because the case literature packet contains no PMIDs and none of these criteria requires a paper-specific finding once the VCEP applicability rules are applied.

5

For this missense variant, PP3 is not met because neither the VCEP's REVEL nor SpliceAI damaging thresholds is reached; BP4 is met at supporting strength through REVEL <=.249; BP7 is not applicable by variant type.

6

Population evidence supports PM2 at supporting strength; BA1 and BS1 are not met, and BS2 is not applicable under the ATM VCEP's incomplete-penetrance rule.

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 1.6 v1.6 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	Not applicable: c.1261T>A is a missense p.Ser421Thr substitution, not one of the ATM VCEP-defined null variant classes eligible for PVS1.	cspec vcep_atm_pvs1_1_6
PS1	Not assessed	Not assessed: no pathogenic same-amino-acid comparator was identified in ATM_PS1_1.6.pdf, although the assessed variant's SpliceAI maximum delta was 0.012.	cspec vcep_atm_ps1_1_6 spliceai
PS2	N/A	Not applicable: the ATM VCEP v1.6 specification explicitly marks PS2 as Not Applicable.	cspec
PS3	Not assessed	Not assessed: Sun et al. directly measured c.1261T>A as Functional, but this assay is not among the VCEP-approved assays and cannot be calibrated to PS3 automatically.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS4	Not assessed	Not assessed: no case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is available to test the VCEP threshold.	cspec
PM1	N/A	Not applicable: the ATM VCEP states that benign and pathogenic variants occur within the same domains and germline hotspots are not well defined.	cspec
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving a highest observed subpopulation frequency of 0%, below the VCEP's ≤0.001% threshold.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband, phenotype classification, second pathogenic variant, or phase evidence is available to assign the VCEP's PM3 points.	vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: p.Ser421Thr is a missense substitution, whereas the ATM VCEP limits PM4 to stop-loss variants.	cspec
PM5	N/A	Not applicable: PM5 is limited to qualifying NMD-prone truncating variants, whereas this variant is missense p.Ser421Thr.	cspec
PM6	N/A	Not applicable: the ATM VCEP v1.6 specification explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation count or parental/family testing result is documented to meet the VCEP's 1-, 2-, or ≥3-relative thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP states that ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: REVEL 0.085 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.012 is below the >=0.2 splice-impact threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP excludes PP4 for ATM breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits use of PP5 under the ClinGen VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax filtering allele frequency above the VCEP's >0.5% threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax filtering allele frequency above the VCEP's >0.05% threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP states that BS2 must not be used because ATM has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: c.1261T>A was directly classified Functional, but the non-approved assay lacks VCEP calibration for assigning BS3 rescue evidence.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:40580951
BS4	N/A	Not applicable: the ATM VCEP v1.6 specification explicitly marks BS4 as Not Applicable.	cspec
BP1	N/A	Not applicable: BP1 is excluded by the ATM VCEP because missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	Not assessed: no unaffected adult, pathogenic co-occurring variant, or cis/trans or homozygous phase observation is available to assign the VCEP's BP2 points.	vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable for this framework.	cspec
BP4	Met	Met at supporting strength: REVEL 0.085 is below the VCEP BP4 missense cutoff of <=0.249.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the VCEP prohibits BP5 because ATM variant co-occurrence does not reliably establish an alternate molecular basis for disease.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits use of BP6 under the ClinGen VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.1261T>A is a missense substitution.	cspec

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