NM_000051.4:c.1355del

ATM · NP_000042.3:p.(Thr452AsnfsTer21) · NM_000051.4

GRCh37: chr11:108121546 AC>A · GRCh38: chr11:108250819 AC>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Thr452AsnfsTer21)

gnomAD AF

1.672765031032889e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.1355del (NP_000042.3:p.Thr452AsnfsTer21) is a frameshift deletion in exon 10 of the ATM gene, creating a premature termination codon at position 472 with predicted nonsense-mediated decay.

PVS1_VeryStrong is applied: the variant is a predicted null allele in a gene where loss of function is an established disease mechanism for ataxia-telangiectasia (autosomal recessive) and cancer susceptibility (autosomal dominant). The PTC is well upstream of p.Arg3047 and the affected exon is constitutive per the ATM VCEP v1.5.0.

PM5_Supporting is applied: the premature termination codon at codon 472 lies upstream of p.Arg3047, the most C-terminal known pathogenic variant in ATM, meeting the VCEP truncation-cutoff rule for PM5_Supporting.

This variant has been reported in ClinVar as Pathogenic by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP (expert panel, reviewed status) and by nine clinical laboratories (8 Pathogenic, 1 Likely pathogenic; ClinVar VariationID 141474).

The variant is extremely rare in population databases: gnomAD v4.1 allele frequency = 0.00167% (27/1,614,094 alleles, 0 homozygotes) and absent from gnomAD v2.1 and gnomAD-Canada v1.0. The grpmax filtering AF of 0.0015% is well below the BA1 (>0.5%) and BS1 (>0.05%) thresholds, confirming the variant is not a common benign polymorphism.

SpliceAI predicts no cryptic splice impact (max delta = 0.02), consistent with the variant exerting its pathogenic effect through protein truncation rather than aberrant splicing.

The variant has been observed in somatic cancers (COSMIC COSV99069690, n=1), consistent with its role as a loss-of-function allele in ATM-related tumorigenesis.

Under the ATM VCEP v1.5.0 combination rules (Richards et al. 2015), the criteria met are PVS1_VeryStrong and PM5_Supporting (1 Pathogenic Very Strong + 1 Pathogenic Supporting). No formal combination rule in the VCEP framework maps exactly to this criterion set; the closest rule (Rule 10: 1 PVS + 1 PM) reaches Likely Pathogenic but requires a Pathogenic Moderate criterion which is not met. However, the ClinGen HBOP VCEP has independently classified this variant as Pathogenic based on their full evidentiary review including proband-level PM3/BP2 data not available in this assessment.

Limitations of this assessment: (a) all five full-text publications retrieved were non-viable (Sci-Hub landing pages without paper content), preventing verification of variant-specific proband counts, segregation data, or functional assay results; (b) PM3 proband-level data referenced by the VCEP expert panel was not available for independent adjudication; (c) PS3/BS3 functional assay results could not be verified.

Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

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	This is a frameshift deletion (c.1355del) in exon 10 of 63, creating a premature termination codon at p.Thr452AsnfsTer21 with predicted nonsense-mediated decay. Loss of function is an established disease mechanism for ATM (ataxia-telangiectasia, autosomal recessive; cancer susceptibility, autosomal dominant). Under the ATM VCEP v1.5.0 PVS1 Decision Tree, this NMD-prone frameshift variant upstream of p.Arg3047 qualifies for PVS1_VeryStrong.	cspec pvs1_generic_framework
PS1	N/A	PS1 under ATM VCEP v1.5.0 applies to missense changes with the same amino acid substitution as a known pathogenic variant, or to splicing variants using the PS1 Splicing table. This is a frameshift deletion and does not fit either category.	cspec
PS2	N/A	ATM VCEP v1.5.0 explicitly states PS2 is not applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not assessed	No variant-specific functional assay data identified for NM_000051.4:c.1355del. OncoKB curates the variant as Likely Loss-of-function, but this is a curated literature gateway and not a direct functional evidence source. All five full-text papers retrieved were non-viable (Sci-Hub landing pages without paper content). Without access to primary functional data, PS3 cannot be assessed.	oncokb
PS4	Not assessed	ATM VCEP v1.5.0 requires formal case-control studies (p<=0.05 AND either OR/HR/RR >=2 or lower 95% CI >=1.5). PS4_Moderate is explicitly not for use. Nine clinical laboratories have submitted this variant as P/LP in ClinVar, suggesting multiple independent proband observations, but no formal case-control study or calibrated proband count has been identified for this variant.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not defined in the ATM VCEP v1.5.0 specifications.
PM1	N/A	ATM VCEP v1.5.0 explicitly states PM1 is not applicable: benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.	cspec
PM2	Not met	The gnomAD v4.1 allele frequency is 0.00167% (27/1,614,094 alleles; grpmax FAF=1.53e-05), which exceeds the ATM VCEP threshold of <=0.001%. While the variant is absent from gnomAD v2.1 and extremely rare overall, the VCEP specifies the v4 dataset exclusively for PM2_Supporting and the observed frequency is above the cutoff.	gnomad_v4
PM4	N/A	ATM VCEP v1.5.0 restricts PM4 to stop-loss variants only. This is a frameshift deletion, not a stop-loss variant. In-frame deletions/insertions less than a single exon are also excluded.	cspec
PM5	Met	This frameshift deletion creates a premature termination codon at p.Thr452AsnfsTer21 (codon 472), which is upstream of p.Arg3047, the most C-terminal known pathogenic variant in ATM. Under ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with PTCs upstream of p.Arg3047.	cspec
PM6	N/A	ATM VCEP v1.5.0 explicitly states PM6 is not applicable: de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not assessed	No segregation data available for this variant. ATM VCEP v1.5.0 limits PP1 to AR condition with both variants identified in proband and affected relatives having both variants. PP1 is not used for the AD condition (low penetrance). All full-text papers were non-viable (Sci-Hub landing pages); no pedigree or co-segregation information could be verified.
PP2	N/A	ATM VCEP v1.5.0 explicitly states PP2 is not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	This is a frameshift deletion, not a missense variant, so the REVEL threshold (>0.7333) does not apply. SpliceAI predicts no significant splice impact (max delta score = 0.02, below the 0.2 threshold for splicing PP3). Additionally, the ATM VCEP notes that PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes.	spliceai cspec
PP4	N/A	ATM VCEP v1.5.0 states PP4 is not applicable: for autosomal dominant, breast cancer has multiple genetic etiologies; for autosomal recessive, such evidence is built into the PM3/BP2 table.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 1.533e-05 (0.0015%), far below the ATM VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 1.533e-05 (0.0015%), below the ATM VCEP BS1 threshold of >0.05%.	gnomad_v4
BS2	N/A	ATM VCEP v1.5.0 explicitly states BS2 is not applicable: ATM has incomplete penetrance.	cspec
BS3	Not assessed	No variant-specific benign functional data identified for NM_000051.4:c.1355del. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect (e.g., rescue of ATM-specific phosphorylation AND radiosensitivity). All available evidence points toward loss of function. Full-text papers were non-viable for verification.
BS4	N/A	ATM VCEP v1.5.0 states BS4 is not applicable: for AD, co-segregation analysis in low-penetrance genes can lead to false positives; for AR, informative instances of lack of co-segregation in A-T families are too rare.	cspec
BP1	N/A	ATM VCEP v1.5.0 explicitly states BP1 is not applicable: missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	BP2 requires observation of this variant in trans with a pathogenic ATM variant in an unaffected individual (aged 18+ with no evidence of A-T). No such data has been identified. The ATM PM3/BP2 table requires proband-level information not available in the current evidence set.
BP3	N/A	ATM VCEP v1.5.0 explicitly states BP3 is not applicable. Additionally, this is a frameshift deletion, not an in-frame deletion in a repetitive region without known function.	cspec
BP4	Not met	While SpliceAI shows no predicted splice impact (max delta = 0.02, below the VCEP BP4 threshold of <=0.1), BP4 is intended to provide benign computational evidence. For a frameshift deletion where the pathogenic mechanism is protein truncation via NMD, the absence of a cryptic splice effect does not constitute benign evidence — the variant is damaging through its primary coding effect. BP4 does not apply.	spliceai
BP5	N/A	ATM VCEP v1.5.0 explicitly states BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with natural co-occurrence of other pathogenic variants.	cspec
BP6	N/A	ATM VCEP v1.5.0 explicitly states BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	ATM VCEP v1.5.0 restricts BP7 to synonymous and deep intronic variants. This is a coding frameshift deletion and does not qualify.	cspec

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