Variant classification summary

NM_000051.4:c.6602T>C

ATM · NP_000042.3:p.(Val2201Ala) · NM_000051.4

GRCh37: chr11:108196066 T>C · GRCh38: chr11:108325339 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Val2201Ala)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

BP4 supporting: REVEL was 0.171 and maximum SpliceAI delta was 0.091, both within the VCEP's benign computational thresholds.

Final determination: Under the ATM VCEP Version 1.6 criteria-combination framework, PM2 supporting plus BP4 supporting satisfies no pathogenic or benign rule, leaving the variant as a 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	N/A	Not applicable: c.6602T>C is a missense substitution, whereas the ATM VCEP PVS1 rule applies to null variant classes such as nonsense, frameshift, splice-site, initiation-codon, or exon-deletion variants.	cspec vcep_atm_pvs1_1_6
PS1	Not assessed	Not assessed: no qualifying previously established pathogenic same-amino-acid comparator was identified for p.Val2201Ala; SpliceAI maximum delta was 0.091.	cspec vcep_atm_ps1_1_6 spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 for AD and AR disease because informative de novo occurrences have not been observed.	cspec
PS3	Not assessed	Not assessed: direct prime-editing classification was Intermediate, which the VCEP table policy assigns neither PS3 nor BS3.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no verified case-control counts, p-value, odds ratio, or confidence interval are available for comparison with the VCEP PS4 rule.	cspec PMID:20301790 PMID:24418350 PMID:25394175 PMID:42258614
PM1	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PM1 as Not Applicable, with no authoritative domain-table entry supplied.	cspec
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to no observed allele and a frequency ≤.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband observation or phase evidence was available to assign the VCEP's per-proband PM3 points.	cspec vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: p.Val2201Ala is a missense substitution, not a stop-loss variant, which is the only variant type named by the ATM VCEP PM4 rule.	cspec
PM5	N/A	Not applicable: PM5 is restricted to specified NMD-prone truncating variants, whereas c.6602T>C is a missense substitution.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
PM6	N/A	Not applicable: the ATM VCEP excludes PM6 for AD and AR disease because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: no affected-relative genotypes or segregation count are documented to evaluate the VCEP's one-, two-, or three-relative thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PP2 as Not Applicable.	cspec
PP3	Not met	Not met: REVEL 0.171 is below >0.7333 and SpliceAI max delta 0.091 is below ≥0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the ATM VCEP prohibits separate PP4 use for both hereditary breast cancer and Ataxia-Telangiectasia phenotype evidence.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly states that PP5 is not for use.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no Grpmax Filtering AF >.5% is present.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no Grpmax Filtering AF >.05% is present.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP states, "Do not use: ATM has incomplete penetrance."	cspec
BS3	Not assessed	Not assessed: direct prime-editing classification was Intermediate, which the VCEP table policy assigns neither PS3 nor BS3.	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 AD segregation can be falsely positive and informative AR non-segregation is too rare for weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no cis/trans observation or unaffected adult proband evidence was available to assign the VCEP's BP2 points.	cspec vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP v1.6 CSPEC explicitly marks BP3 as Not Applicable for this framework.	cspec
BP4	Met	Met: REVEL 0.171 is at or below the VCEP missense cutoff of ≤0.249.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants may coexist without a noticeable phenotype difference.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly states that BP6 is not for use.	cspec
BP7	N/A	Not applicable: ATM c.6602T>C is a missense substitution, not a synonymous or deep intronic variant.	cspec

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