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.