Variant classification summary

NM_000051.4:c.8315del

ATM · NP_000042.3:p.(Gly2772GlufsTer34) · NM_000051.4

GRCh37: chr11:108213993 AG>A · GRCh38: chr11:108343266 AG>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.(Gly2772GlufsTer34)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.8315del (p.Gly2772GlufsTer34) variant has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.

2

This variant is absent from gnomAD v4.1 and gnomAD v2.1, supporting rarity in the general population.

3

ATM-specific criteria support pathogenic evidence for this truncating variant because p.(Gly2772GlufsTer34) introduces a premature termination codon upstream of the p.Arg3047 threshold used for ATM truncating variants, and ATM loss of function is an established disease mechanism.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.14.

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 variant is a frameshift deletion, NM_000051.4:c.8315del, predicted to cause p.(Gly2772GlufsTer34). ATM-specific guidance permits PVS1 for loss-of-function variants, and this variant is not in a context that would withhold PVS1 under the available ATM loss-of-function framework.	cspec pvs1_gene_context pvs1_variant_assessment vcep_a_t_m___p_v_s_1___1___5
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of less than or equal to 0.001% in gnomAD v4.	cspec gnomad_v4 gnomad_v2
PM5	Met	ATM-specific guidance allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Arg3047. This variant causes p.(Gly2772GlufsTer34), which truncates the protein upstream of p.Arg3047 and therefore meets that ATM-specific positional rule.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the ATM BA1 threshold of greater than 0.5%.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the ATM BS1 threshold of greater than 0.05%.	cspec gnomad_v4
BS2	N/A	Available ATM-specific specifications do not use BS2 because ATM-related disease shows incomplete penetrance.	cspec
BS3	Not assessed	ATM-specific functional criteria require a validated rescue assay showing rescue of ATM-specific function and/or radiosensitivity. No variant-specific rescue data meeting these ATM BS3 requirements were identified for this variant.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448
BS4	N/A	Available ATM-specific specifications do not use BS4 for ATM because segregation analysis is not considered reliable for this low-penetrance context, and lack of segregation in A-T families is not assigned independent weight.	cspec
BP1	N/A	Available ATM-specific specifications do not use BP1 because pathogenic missense variants are known in ATM.	cspec
BP2	Not assessed	ATM-specific BP2 requires documented co-occurrence in trans or homozygosity in an unaffected person under the ATM PM3/BP2 point framework. No qualifying phase or unaffected co-occurrence data were identified for this variant.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
BP3	N/A	Available ATM-specific specifications do not use BP3.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact with a maximum delta score of 0.14, but this value is above the ATM BP4 splicing threshold of less than or equal to 0.1. The variant is also a frameshift rather than a missense change for REVEL-based assessment.	cspec spliceai
BP5	N/A	Available ATM-specific specifications do not use BP5.	cspec
BP6	N/A	Available ATM-specific specifications do not use BP6.	cspec
BP7	N/A	BP7 is reserved for synonymous or deep intronic variants, or for RNA studies showing lack of splice defect in those variant classes. This variant is an exonic frameshift deletion, so BP7 does not apply.	cspec
PP1	Not assessed	ATM-specific PP1 requires segregation data in affected relatives for the recessive condition framework. No qualifying segregation data were identified for this variant.	cspec
PP2	N/A	Available ATM-specific specifications do not use PP2 because ATM does not have a sufficiently constrained missense profile for this rule.	cspec
PP3	Not met	SpliceAI predicts a maximum delta score of 0.14. This value is below the ATM PP3 splicing threshold of greater than or equal to 0.2, so available computational splicing evidence does not support PP3 for this variant.	cspec spliceai
PP4	N/A	Available ATM-specific specifications do not use PP4 as an independent line of evidence for ATM.	cspec
PP5	N/A	Available ATM-specific specifications do not use PP5.	cspec
PS1	N/A	PS1 is intended for the same amino acid change as a known pathogenic variant or for defined splice-event matches in the ATM PS1 splicing framework. This variant is a frameshift deletion, and no same-effect PS1 match was identified.	cspec vcep_a_t_m___p_s_1___1___5
PS2	N/A	Available ATM-specific specifications do not use PS2 for ATM.	cspec
PS3	Not assessed	ATM-specific functional criteria require a validated assay showing failure to rescue ATM-specific function, with or without radiosensitivity depending on strength. Available sources cited functional literature, but no variant-specific ATM assay result meeting these PS3 requirements was identified for this variant.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study data were identified showing a p-value less than or equal to 0.05 together with an odds ratio, hazard ratio, or relative risk of at least 2, or a lower 95% confidence interval of at least 1.5. Therefore PS4 is not established from the available evidence.	cspec clinvar
PM1	N/A	Available ATM-specific specifications do not use PM1 because germline mutational hotspots are not sufficiently defined for ATM.	cspec hotspots
PM3	Not assessed	ATM-specific PM3 requires qualifying observations in trans with a pathogenic or likely pathogenic ATM variant, scored under the ATM PM3/BP2 point framework. No qualifying phase-confirmed or point-scored recessive observations were identified for this variant.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
PM4	N/A	ATM-specific PM4 is reserved for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply.	cspec
PM6	N/A	Available ATM-specific specifications do not use PM6 for ATM.	cspec

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