Variant classification summary

NM_000051.4:c.2552A>G

ATM · NP_000042.3:p.(Asp851Gly) · NM_000051.4

GRCh37: chr11:108137983 A>G · GRCh38: chr11:108267256 A>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asp851Gly)

gnomAD AF

1.4869980607066958e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 (Supporting): REVEL 0.099 falls below the <=0.249 benign missense threshold, favoring a benign impact.

2

Final classification VUS: with BP4 Supporting as the only applied criterion, no benign or pathogenic combination rule under ATM VCEP v1.5 is satisfied.

Final determination: Under the ATM VCEP v1.5 criteria-combination framework, one benign supporting criterion alone matches no final-classification rule, so the final call is VUS.

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	Not met	Not met: c.2552A>G is a missense substitution (p.Asp851Gly) that creates no premature termination codon.	cspec vcep_atm_pvs1_1_5
PS1	Not met	Not met: no established pathogenic or likely pathogenic p.Asp851Gly comparator exists for this same amino-acid change.	vcep_atm_ps1_1_5 cspec clinvar spliceai PMID:26976419
PS2	N/A	Not applicable: the ATM VCEP v1.5 excludes de novo evidence for autosomal dominant and recessive ATM disease.	cspec
PS3	Not assessed	Not assessed: no VCEP-approved assay evidence indicates loss of function; Sun et al. 2025 labels the variant Functional but is not VCEP-calibrated.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec
PS4	Not assessed	Not assessed: the sole report (PMID:26976419) gives no case-control counts or association statistic for c.2552A>G.	cspec PMID:26976419
PM1	N/A	Not applicable: the ATM VCEP v1.5 explicitly marks PM1 non-applicable, with no approved ATM domain table.	cspec
PM2	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00103% narrowly exceeds the PM2 <=0.001% threshold.	cspec gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no ataxia-telangiectasia phenotype, second ATM variant, or phase data are available to assign PM3 points.	cspec vcep_atm_pm3_bp2_1_5 PMID:26976419
PM4	Not met	Not met: PM4 applies only to stop-loss variants; p.Asp851Gly is a missense with no protein-length change.	cspec
PM5	N/A	Not applicable: the VCEP PM5 rule is restricted to truncating and qualifying splice variants, not missense variants.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP v1.5 specifies PM6 non-applicable; de novo occurrences are not informative for ATM disease.	cspec
PP1	Not assessed	Not assessed: no segregation data (affected relatives, phase, or informative meioses) are documented for c.2552A>G.	cspec PMID:26976419
PP2	N/A	Not applicable: the ATM VCEP v1.5 explicitly marks PP2 non-applicable.	cspec
PP3	Not met	Not met: REVEL 0.099 is far below the PP3 >0.7333 threshold (SpliceAI max delta 0.074 is also below 0.2).	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP v1.5 explicitly declares PP4 non-applicable.	cspec
PP5	N/A	Not applicable: no ClinVar expert-panel pathogenic assertion exists; all submissions are from laboratories.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00103% is far below the BA1 >0.5% threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.00103% is below the BS1 >0.05% threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP v1.5 framework marks BS2 non-applicable.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no VCEP-approved functional assay result is available for p.Asp851Gly. Flagged for human review: an uncalibrated prime-editing dataset labels the variant Functional, which could support BS3 once VCEP-calibrated.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec
BS4	N/A	Not applicable: the ATM VCEP v1.5 specifies BS4 non-applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP v1.5 explicitly marks BP1 non-applicable.	cspec
BP2	Not assessed	Not assessed: no unaffected non-A-T carrier with a pathogenic variant in trans and known phase is documented.	cspec vcep_atm_pm3_bp2_1_5 PMID:26976419
BP3	N/A	Not applicable: BP3 is designated non-applicable in the ATM VCEP v1.5 specification.	cspec
BP4	Met	Met (Supporting): REVEL 0.099 meets the BP4 <=0.249 benign missense threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP v1.5 explicitly declares BP5 non-applicable.	cspec
BP6	N/A	Not applicable: the sole Likely benign ClinVar submission is from a single laboratory, not an expert panel.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers synonymous and deep-intronic variants; p.Asp851Gly is missense.	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.