Variant classification summary

NM_000051.4:c.5937A>G

ATM · NP_000042.3:p.(Glu1979=) · NM_000051.4

GRCh37: chr11:108183156 A>G · GRCh38: chr11:108312429 A>G

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting PP3 supporting BS3 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Glu1979=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS3 supporting reflects high-confidence functional data classifying c.5937A>G as Functional.

2

Likely Benign: BP7 supporting applies because c.5937A>G is synonymous.

3

Supporting evidence: PM2 reflects absence from available gnomAD datasets.

4

Supporting evidence: PP3 reflects a SpliceAI maximum delta of 0.247.

Final determination: ATM VCEP Version 1.6 Rule19 classifies the variant as Likely Benign when at least two benign supporting criteria are present; BS3 supporting and BP7 supporting satisfy 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: c.5937A>G is synonymous (p.Glu1979=), while the ATM PVS1 guide covers null variants and no observed RNA defect is available.	cspec vcep_atm_pvs1_1_5 spliceai
PS1	Not assessed	Not assessed: SpliceAI max delta 0.247 exceeds the 0.2 splice-impact threshold, but no matching pathogenic reference event was found for the VCEP PS1 comparison.	cspec spliceai vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP explicitly excludes PS2 for autosomal dominant and autosomal recessive disease.	cspec
PS3	Not met	Not met: Table S1 classifies c.5937A>G as Functional with high confidence, not as a loss-of-function result qualifying for ATM PS3.	cspec vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no variant-specific case-control study, p-value, odds ratio, relative risk, hazard ratio, or confidence interval is available.	cspec
PM1	N/A	Not applicable: the ATM VCEP marks PM1 not applicable, and this variant is synonymous rather than a domain- or hotspot-based missense change.	cspec
PM2	Met	Met at Supporting: variant absent from gnomAD v2.1/v4.1 and non-cancer subsets, satisfying ATM VCEP's ≤0.001% highest-subpopulation frequency rule.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, homozygous, second-allele, or phase observation was available to assign the VCEP's PM3 points.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: p.Glu1979= is synonymous and does not produce the stop-loss protein-length change required by the ATM PM4 rule.	cspec
PM5	N/A	Not applicable: ATM PM5 is restricted to qualifying truncating variants upstream of p.Leu3048, whereas c.5937A>G is synonymous.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP explicitly excludes PM6 for autosomal dominant and autosomal recessive disease.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation, parental testing, or meiosis count is documented for applying the ATM VCEP PP1 thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 not applicable, and c.5937A>G is synonymous rather than missense.	cspec
PP3	Met	Met at supporting: SpliceAI maximum delta 0.247 meets the ATM VCEP PP3 threshold of >=0.2 for predicted splice impact.	cspec spliceai
PP4	N/A	Not applicable: the ATM HBOP VCEP v1.6 explicitly designates PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the ATM VCEP excludes PP5, and ClinVar has zero expert-panel submissions for this exact variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.05%.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: ATM VCEP v1.6 excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Met	Met, Supporting: direct prime-editing data classify c.5937A>G as Functional with high confidence, but VCEP acceptance of this non-approved assay requires human review.	cspec vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable: the ATM VCEP explicitly excludes BS4, so non-segregation cannot receive this criterion.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 not applicable, and c.5937A>G is synonymous rather than missense.	cspec
BP2	Not assessed	Not assessed: no unaffected adult co-occurrence with a pathogenic ATM allele or phase evidence was available to assign the VCEP's BP2 points.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP marks BP3 unavailable, and c.5937A>G is synonymous rather than an in-frame repeat-region insertion or deletion.	cspec
BP4	Not met	Not met: SpliceAI maximum delta 0.247 exceeds the ATM VCEP BP4 no-impact threshold of <=0.1.	cspec spliceai
BP5	N/A	Not applicable: the ATM HBOP VCEP v1.6 explicitly designates BP5 as not applicable.	cspec
BP6	N/A	Not applicable: the ATM VCEP excludes BP6, and ClinVar has only ordinary laboratory assertions with zero expert-panel submissions.	cspec clinvar
BP7	Met	Met at supporting: ATM VCEP v1.6 assigns BP7 supporting to synonymous variants, and this variant is c.5937A>G (p.Glu1979=).	cspec spliceai

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.