Variant classification summary

NM_000051.4:c.8735_8751del

ATM · NP_000042.3:p.(Arg2912AsnfsTer7) · NM_000051.4

GRCh37: chr11:108224555 AGAGATATTGTGGATGGC>A · GRCh38: chr11:108353828 AGAGATATTGTGGATGGC>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2912AsnfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports a loss-of-function ATM truncation upstream of the VCEP pathogenic boundary.

2

Pathogenic: PM2 supporting reflects the variant's absence from gnomAD v2.1 and v4.1.

3

Pathogenic: PM5 supporting applies because the truncation ends upstream of ATM p.Leu3048 with PVS1 very strong.

Final determination: ATM VCEP Version 1.6 Rule4 classifies a variant as Pathogenic when one Pathogenic.Very Strong criterion is combined with at least two Pathogenic.Supporting criteria.

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	Met	Met at very strong: the 17-nucleotide deletion causes p.Arg2912AsnfsTer7, truncating ATM 139 residues before its 3057-residue normal length and upstream of the VCEP p.Arg3047 boundary.	cspec vcep_atm_pvs1_1_5
PS1	N/A	Not applicable: ATM VCEP PS1 covers missense or splice-region variants, whereas this variant is a frameshift producing p.Arg2912AsnfsTer7.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 for both autosomal-dominant and autosomal-recessive disease because informative de novo occurrences are not established.	cspec
PS3	Not assessed	Not assessed: no variant-specific result was found in the approved ATM functional assays, and the 17-base deletion is absent from the SNV functional table.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	Not met: no qualifying case-control p-value, effect estimate, confidence interval, or validated proband-count evidence was reported for this exact deletion.	cspec
PM1	N/A	Not applicable: ATM VCEP v1.6 marks PM1 as not applicable, and this frameshift is not a missense change assessed by a critical-domain rule.	cspec
PM2	Met	Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0 versus the ATM VCEP PM2 threshold of <=0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband, pathogenic variant in trans, phase information, or qualifying homozygous observation is documented for this variant.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	Not applicable: ATM VCEP PM4 is reserved for stop-loss variants, whereas this variant is a frameshift producing a premature stop at p.Asn2918.	cspec
PM5	Met	Met at supporting strength: the truncating product ends at approximately p.Asn2918, upstream of the ATM VCEP PM5 cutoff p.Leu3048, with PVS1 provisionally very strong.	cspec pvs1_gene_context pvs1_variant_assessment
PM6	N/A	Not applicable: the ATM VCEP excludes PM6 for both autosomal-dominant and autosomal-recessive disease because assumed de novo evidence is not informative.	cspec
PP1	Not assessed	Not assessed: zero affected relatives with documented segregation are available, below the ATM VCEP threshold of one affected relative for PP1 Supporting.	cspec
PP2	N/A	Not applicable: ATM VCEP v1.6 explicitly marks PP2 as not applicable for this gene framework.	cspec
PP3	N/A	Not applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside PP3's calibrated missense or splicing scope.	cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP prohibits separate PP4 use because cancer is genetically heterogeneous and ataxia-telangiectasia phenotype is incorporated into PM3/BP2.	cspec
PP5	Not met	Not met: ClinVar contains no exact-variant expert-panel Pathogenic or Likely pathogenic classification for NM_000051.4:c.8735_8751del.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the ATM VCEP BA1 threshold of >0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the ATM VCEP BS1 threshold of >0.05%.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM HBOP VCEP version 1.6 explicitly designates BS2 as not applicable.	cspec
BS3	Not assessed	Not assessed: no variant-specific benign functional result was found in the approved ATM assays, and the 17-base deletion is absent from the SNV functional table.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: the ATM VCEP assigns no BS4 weight because informative non-segregation is too rare in A-T and low penetrance confounds AD segregation.	cspec
BP1	N/A	Not applicable: ATM VCEP v1.6 explicitly marks BP1 as not applicable for this gene framework.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrier with a pathogenic or likely pathogenic ATM variant in trans, phase, or setting is documented.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: ATM VCEP marks BP3 as unavailable, and this variant is a truncating frameshift rather than an in-frame repeat-region deletion.	cspec
BP4	N/A	Not applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside BP4's calibrated missense, intronic, synonymous, or splice-region scope.	cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP v1.6 explicitly designates BP5 as not applicable for this gene and disease framework.	cspec
BP6	N/A	Not applicable: ATM VCEP v1.6 prohibits BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), not a synonymous or qualifying deep-intronic variant for BP7.	cspec

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