Variant classification summary

NM_000051.4:c.6317A>T

ATM · NP_000042.3:p.(Asn2106Ile) · NM_000051.4

GRCh37: chr11:108188218 A>T · GRCh38: chr11:108317491 A>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asn2106Ile)

gnomAD AF

6.825879266329675e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (supporting) met: the variant is below the ATM VCEP's 0.001% frequency ceiling in every gnomAD population (group-max filtering AF 0.000292%), with no homozygotes observed.

2

No pathogenic combination reached: PM2 supporting alone falls short of the weakest ATM VCEP pathogenic rule, which requires one moderate plus four supporting criteria.

3

No benign combination reached: no benign criterion is met at any strength, so the benign and conflicting-evidence rules cannot fire.

Final determination: Under the ATM VCEP v1.6 criteria-combination framework, a single supporting-strength pathogenic criterion (PM2) satisfies no pathogenic or likely pathogenic rule and no benign rule is satisfied, so the default outcome is a Variant of Uncertain Significance.

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.6317A>T is a mid-exonic missense change (p.Asn2106Ile, exon 43, SpliceAI max delta 0.005), not a null variant covered by the ATM VCEP PVS1 decision tree.	cspec vcep_atm_pvs1_1_5 vcep_atm_pvs1_1_6 vcep_suppl_tables1_pmid_40580951 spliceai
PS1	Not met	Not met: no established pathogenic variant shares the p.Asn2106Ile change (ClinVar 135768 is a 2-star VUS) and SpliceAI max delta 0.005 bars the splicing table.	cspec vcep_atm_ps1_1_5 vcep_atm_ps1_1_6 spliceai clinvar pm5_candidates vcep_suppl_tables1_pmid_40580951
PS2	N/A	Not applicable: the ATM VCEP v1.6 prohibits PS2 for ATM disease because informative de novo occurrences have not been observed.	cspec
PS3	Not met	Not met: the only functional result is the Sun 2025 prime-editing screen (PMID 40580951), which scores this variant Functional, and no VCEP-approved kinase or radiosensitivity assay was reported.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 clinvar oncokb PMID:25741868
PS4	Not met	Not met: no case-control odds ratio, hazard ratio or relative risk is reported for ATM c.6317A>T, so the VCEP's OR >=2 (or lower CI >=1.5) threshold has nothing to satisfy it.	cspec clinvar
PM1	N/A	Not applicable: the ATM VCEP marks PM1 'Not applicable' with the direction not to use it, as benign and pathogenic variants co-occur in the same domains.	cspec
PM2	Met	Met at supporting: gnomAD v4.1 group-max filtering AF 0.000292% in European (non-Finnish) is below the VCEP 0.001% threshold, with zero homozygotes.	cspec gnomad_v4 gnomad_v2 gnomad_canada PMID:25741868
PM3	Not assessed	Not assessed: no A-T proband carries c.6317A>T with a second ATM pathogenic variant in trans, so the VCEP table's minimum 1.0 PM3 point is unattainable.	cspec vcep_atm_pm3_bp2_1_5 vcep_atm_pm3_bp2_1_6 gnomad_v4 gnomad_v2 clinvar
PM4	N/A	Not applicable: the ATM VCEP limits PM4 to stop-loss variants, and p.Asn2106Ile is a single missense substitution in exon 43 with no protein-length change.	cspec vcep_suppl_tables1_pmid_40580951
PM5	N/A	Not applicable: ATM VCEP PM5_Supporting covers only truncating variants upstream of p.Leu3048 and explicitly excludes missense changes such as p.Asn2106Ile.	cspec pm5_candidates clinvar vcep_suppl_tables1_pmid_40580951
PM6	N/A	Not applicable: the ATM VCEP v1.6 prohibits PM6, as no informative de novo occurrences are available to calibrate it for ATM disease.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregations are documented for this variant, versus the ATM VCEP threshold of one affected relative for PP1 supporting.	cspec clinvar PMID:25741868 PMID:24418350 PMID:25394175
PP2	N/A	Not applicable: the ATM VCEP marks PP2 'Not applicable' with the direction not to use it, because ATM has no defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: missense REVEL 0.539 sits in the gray zone, below the ATM VCEP PP3 threshold of REVEL >0.7333.	cspec revel vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP excludes PP4 at every strength, and no patient phenotype or family history accompanies this variant.	cspec
PP5	Not met	Not met: ClinVar VCV000135768 is Uncertain significance at two stars with five ordinary laboratory submissions and zero expert-panel submissions.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 group-max filtering AF 0.000292% is roughly 1,700-fold below the VCEP stand-alone benign threshold of 0.5%.	cspec gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: the highest gnomAD frequency, group-max filtering AF 0.000292%, is about 170-fold below the VCEP strong benign threshold of 0.05%.	cspec gnomad_v4 gnomad_v2 PMID:25741868
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM-related disease is incompletely penetrant, and no homozygous carrier appears in gnomAD.	cspec
BS3	Not met	Not met: the prime-editing screen directly measures this variant as Functional (Combined score -0.754, above the -0.912 Functional boundary), but that assay is not a VCEP-approved or calibrated ATM test.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 clinvar oncokb PMID:25741868
BS4	N/A	Not applicable: the ATM VCEP v1.6 excludes BS4, because informative lack of co-segregation in A-T families is too rare to carry weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 'Not applicable' with the direction not to use it, because missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carries c.6317A>T in trans or cis with a pathogenic ATM variant, so no negative BP2 points from the VCEP table can be assigned.	cspec vcep_atm_pm3_bp2_1_5 vcep_atm_pm3_bp2_1_6 gnomad_v4 gnomad_v2 clinvar
BP3	N/A	Not applicable: the ATM VCEP marks BP3 'Not Applicable' and p.Asn2106Ile is a substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: missense REVEL 0.539 exceeds the ATM VCEP BP4 cutoff of REVEL <=0.249, and the clean SpliceAI score cannot substitute.	cspec revel vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP excludes BP5 because ATM is low penetrance and co-occurring pathogenic variants show no phenotype difference.	cspec
BP6	Not met	Not met: no expert-panel submission or Benign classification exists for c.6317A>T; VCV000135768 is Uncertain significance at two stars.	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous and deep intronic variants, and c.6317A>T is a missense change (p.Asn2106Ile).	cspec vcep_suppl_tables1_pmid_40580951

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.