Variant classification summary

NM_000051.4:c.4424A>c

ATM · NP_000042.3:p.(Tyr1475Ser) · NM_000051.4

GRCh37: chr11:108160516 A>C · GRCh38: chr11:108289789 A>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting BS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Tyr1475Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

2

BS3 supporting: direct prime-editing classified c.4424A>C (Y1475S) as Functional with medium-high confidence.

3

BP4 supporting: SpliceAI maximum delta 0.005 is at or below the VCEP's 0.1 threshold for no predicted splice impact.

Final determination: Under Rule19 of the ATM VCEP Version 1.6 framework, at least two benign Supporting criteria (BS3 and BP4) yield Likely Benign; PM2 Supporting does not independently satisfy a pathogenic 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: c.4424A>C is a missense variant, whereas the ATM PVS1 rule applies to specified null-variant classes.	cspec vcep_atm_pvs1_1_6
PS1	Not assessed	Not assessed: no governing-table entry or established same-amino-acid pathogenic comparator was available for p.Tyr1475Ser, despite a maximum SpliceAI delta of 0.005.	cspec vcep_atm_ps1_1_6 spliceai
PS2	N/A	Not applicable: the ATM VCEP prohibits PS2 for both dominant and recessive disease because informative de novo occurrences have not been observed.	cspec
PS3	Not met	Not met: direct prime-editing classified c.4424A>C as Functional with Medium-high confidence, opposite the VCEP PS3 requirement for failure to rescue an ATM-specific feature.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no case-control paper or variant-specific affected-versus-control counts were available to calculate p-value, odds ratio, or 95% CI.	cspec
PM1	N/A	Not applicable: the ATM VCEP marks PM1 Not Applicable, and its authoritative domain_tables entry is empty for this gene.	cspec
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP's ≤0.001% highest-subpopulation-frequency threshold.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, phenotype, second-variant, or phase evidence was available to assign the ATM VCEP's PM3 points.	vcep_atm_pm3_bp2_1_6 cspec
PM4	N/A	Not applicable: p.Tyr1475Ser is a missense substitution, not the stop-loss variant type specified by the ATM VCEP PM4 rule.	cspec
PM5	N/A	Not applicable: PM5 is restricted to qualifying NMD-prone truncating variants upstream of p.Leu3048, whereas this variant is missense p.Tyr1475Ser.	cspec
PM6	N/A	Not applicable: the ATM VCEP prohibits PM6 for both dominant and recessive disease because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregation data are available to evaluate the VCEP requirement that both variants be identified in the proband.	cspec
PP2	N/A	Not applicable: the ATM VCEP explicitly designates PP2 Not Applicable for this framework.	cspec
PP3	Not met	Not met: REVEL 0.284 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.005 is below the ≥0.2 threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the ATM VCEP v1.6 criterion entry explicitly marks PP4 as Not Applicable.	cspec
PP5	N/A	Not applicable: the ATM VCEP v1.6 criterion entry explicitly marks PP5 as Not Applicable.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP's >0.5% grpmax allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP's >0.05% grpmax allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP prohibits BS2 because ATM has incomplete penetrance.	cspec
BS3	Met	Met at Supporting: direct prime-editing classified c.4424A>C as Functional with Medium-high confidence and DeepATM_predicted=No, satisfying the VCEP BS3 mapping.	cspec 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-co-segregation instances in ataxia-telangiectasia families are too rare for weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly designates BP1 Not Applicable for this framework.	cspec
BP2	Not assessed	Not assessed: no unaffected-adult observation or cis/trans relationship with a pathogenic ATM variant was documented for BP2.	vcep_atm_pm3_bp2_1_6 cspec
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable, and this variant is missense rather than an in-frame repeat-region indel.	cspec
BP4	Met	Met at Supporting: SpliceAI max delta 0.005 is ≤0.1 for the VCEP's no-predicted-splice-impact BP4 path, despite REVEL 0.284.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP v1.6 criterion entry explicitly marks BP5 as Not Applicable.	cspec
BP6	N/A	Not applicable: the ATM VCEP v1.6 criterion entry explicitly marks BP6 as Not Applicable.	cspec
BP7	N/A	Not applicable: c.4424A>C is an exonic missense variant, while the VCEP limits BP7 to synonymous and deep intronic variants.	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.