Variant classification summary

NM_000051.4:c.6897C>T

ATM · NP_000042.3:p.(Phe2299=) · NM_000051.4

GRCh37: chr11:108196874 C>T · GRCh38: chr11:108326147 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS3 supporting BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Phe2299=)

gnomAD AF

2.0446780747311248e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign evidence: high-confidence direct prime-editing classified the exact variant as Functional, satisfying BS3 Supporting.

2

Benign evidence: SpliceAI maximum delta score 0.009 is below the VCEP BP4 threshold of 0.1, satisfying BP4 Supporting.

3

Benign evidence: the synonymous c.6897C>T consequence satisfies the VCEP's BP7 Supporting scope.

Final determination: ATM VCEP Version 1.6 Rule19 classifies a variant as Likely Benign when at least two benign supporting criteria are satisfied; BS3, BP4, and BP7 meet this rule.

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: the variant is synonymous and SpliceAI maximum delta score is 0.009, with no predicted or observed splice defect supporting ATM PVS1.	cspec vcep_atm_pvs1_1_6 spliceai
PS1	N/A	Not applicable: c.6897C>T is synonymous (p.Phe2299=), and ATM_PS1_1.6.pdf contains no matching variant entry.	cspec vcep_atm_ps1_1_6
PS2	N/A	Not applicable: the ATM VCEP states that informative de novo occurrences have not been observed for either autosomal-dominant or autosomal-recessive disease.	cspec
PS3	Not met	Not met: direct prime-editing classified c.6897C>T as Functional with High confidence, not a variant failing to rescue an ATM-specific feature.	vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no variant-specific case-control p-value, odds ratio, relative risk, hazard ratio, or lower 95% confidence interval is available for the PS4 thresholds.	cspec
PM1	N/A	Not applicable: ATM Version 1.6 marks PM1 as Not Applicable, and no authoritative ATM domain-table entry is present.	cspec
PM2	Not met	Not met: the highest gnomAD subpopulation AF is 0.00271185% in v4.1, exceeding the VCEP's ≤0.001% PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no governing-table entry or affected A-T proband phase evidence is available to assign PM3 points.	cspec vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: p.(Phe2299=) is synonymous and does not represent the VCEP-defined PM4 stop-loss variant type.	cspec
PM5	N/A	Not applicable: PM5 requires an NMD-prone truncating or qualifying splice variant upstream of p.Leu3048, whereas this variant is synonymous.	cspec
PM6	N/A	Not applicable: the ATM VCEP states that informative de novo occurrences have not been observed for either autosomal-dominant or autosomal-recessive disease.	cspec
PP1	Not assessed	Not assessed: no affected relatives, parental testing, phase information, or segregation count is documented to meet the VCEP's AR PP1 requirements.	cspec
PP2	N/A	Not applicable: the ATM Version 1.6 CSPEC explicitly marks PP2 as Not Applicable.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score 0.009 is below the VCEP PP3 threshold of 0.2.	cspec spliceai
PP4	N/A	Not applicable: the VCEP excludes PP4 for hereditary breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits PP5, regardless of the available ClinVar classifications or literature references.	cspec
BA1	Not met	Not met: gnomAD grpmax filtering AF is 0.001962% in v4.1, below the VCEP's >0.5% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD grpmax filtering AF is 0.001962% in v4.1, below the VCEP's >0.05% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance, regardless of zero observed homozygotes.	cspec
BS3	Met	Met at Supporting: direct prime-editing classified c.6897C>T as Functional with High confidence and DeepATM_predicted=No.	vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable: the ATM VCEP excludes BS4 because informative lack-of-segregation instances in A-T families are too rare for weight.	cspec
BP1	N/A	Not applicable: the ATM Version 1.6 CSPEC explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no governing-table entry or qualifying unaffected adult cis/trans observation is available to assign BP2 points.	cspec vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable and instructs curators not to use it.	cspec
BP4	Met	Met: SpliceAI maximum delta score 0.009 is at or below the VCEP BP4 threshold of 0.1.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP explicitly says not to use BP5 because multiple pathogenic variants may coexist without a noticeable phenotype difference.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits BP6, regardless of the available ClinVar benign or likely benign submissions.	cspec
BP7	Met	Met: The variant is synonymous (p.Phe2299=), which is explicitly within the VCEP BP7 supporting scope.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.