Variant classification summary

NM_000051.4:c.7592T>C

ATM · NP_000042.3:p.(Met2531Thr) · NM_000051.4

GRCh37: chr11:108202247 T>C · GRCh38: chr11:108331520 T>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Met2531Thr)

gnomAD AF

4.896904660365569e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: high-confidence direct prime-editing classified c.7592T>C as functional, satisfying BS3 Supporting.

2

Likely Benign: REVEL 0.196 is below the ATM VCEP BP4 missense cutoff, satisfying BP4 Supporting.

Final determination: Under the ATM VCEP Version 1.6 Rule19, at least two supporting benign criteria satisfy the Likely Benign combination; here those criteria are BS3 Supporting and BP4 Supporting.

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.7592T>C is a missense SNV in exon 51, whereas the ATM VCEP PVS1 rule applies to specified null variants rather than ordinary missense substitutions.	cspec vcep_atm_pvs1_1_6
PS1	Not assessed	Not assessed: no same-amino-acid established pathogenic comparator and no qualifying evidence ruling out splicing for both missense alterations.	cspec vcep_atm_ps1_1_6
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 for autosomal-dominant and autosomal-recessive disease because informative de novo occurrences have not been observed.	cspec
PS3	Not met	Not met: direct prime-editing classified c.7592T>C as Functional with High confidence, not as a variant that fails to rescue ATM function.	vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: the available case-control paper reports ATM missense classes, not this variant, so variant-specific p-value, effect estimate, and 95% confidence interval are unavailable.	cspec PMID:19781682
PM1	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PM1 as Not Applicable for this framework.	cspec
PM2	Not met	Not met: the highest gnomAD v4.1 subpopulation frequency is 0.00644213%, exceeding the VCEP PM2 threshold of <=0.001%.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected A-T proband, second allele, or phase information is available to assign the VCEP's PM3 points.	vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: p.(Met2531Thr) is a missense substitution, not a stop-loss variant, so it does not meet the ATM VCEP PM4 applicability rule.	cspec
PM5	N/A	Not applicable: PM5 is restricted to qualifying NMD-prone truncating variants upstream of p.Leu3048, whereas this is missense p.Met2531Thr.	cspec
PM6	N/A	Not applicable: the ATM VCEP excludes PM6 for autosomal-dominant and autosomal-recessive disease because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation or parental-phase result is documented, so the VCEP's 1-, 2-, or ≥3-relative PP1 thresholds cannot be evaluated.	cspec
PP2	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PP2 as Not Applicable.	cspec
PP3	Not met	Not met: REVEL 0.196 is below the VCEP PP3 missense threshold of >.7333, and SpliceAI max delta 0.004 is below its >=0.2 splice threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP excludes PP4 for breast cancer and prohibits separate PP4 use for ataxia-telangiectasia.	cspec
PP5	N/A	Not applicable: the ATM VCEP prohibits PP5 regardless of reputational-source classifications.	cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.005276%, below the VCEP BA1 threshold of >0.5%.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.005276%, below the VCEP BS1 threshold of >0.05%.	cspec gnomad_v4 gnomad_v2
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.7592T>C 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 assigns no BS4 weight because informative lack-of-segregation instances in ataxia-telangiectasia families are too rare.	cspec
BP1	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no unaffected adult, pathogenic co-occurring variant, or cis/trans phase observation is available for the VCEP's BP2 points assignment.	vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable, and c.7592T>C is a missense SNV rather than an in-frame indel in a repetitive region.	cspec
BP4	Met	Met at Supporting: REVEL 0.196 is below the VCEP BP4 missense cutoff of <=.249.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants can occur without a distinct phenotype and ATM has low penetrance.	cspec
BP6	N/A	Not applicable: the ATM VCEP prohibits BP6 regardless of reputable-source benign classifications.	cspec
BP7	N/A	Not applicable: c.7592T>C is an exonic missense variant, whereas the VCEP BP7 scope is synonymous or deep intronic variants.	cspec

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