NM_000051.4:c.8418+5_8418+8delGTGA

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108214098 GGTGA>G · GRCh38: chr11:108343371 GGTGA>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.8418+5_8418+8del (NP_000042.3:p.?) variant has not been reported in ClinVar.

This variant is present in gnomAD v4.1 at AF 0.00465% (75/1,613,598 alleles; grpmax FAF 0.005111%) and in gnomAD v2.1 at AF 0.00071% (2/282,394 alleles), which is above the ATM PM2_Supporting threshold of 0.001% and below the BS1 threshold of 0.05%.

SpliceAI predicts an adverse splicing effect with a maximum delta score of 0.89, which exceeds the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions and supports PP3.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not assessed	This intronic donor-region deletion is outside the canonical ±1,2 splice positions, so it is not covered by the default generic null-variant scaffold. ATM loss of function is an established disease mechanism, but the available evidence does not show the exact RNA consequence for this variant or confirm whether any abnormal transcript is NMD-prone under the ATM PVS1 decision framework.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No previously established pathogenic or likely pathogenic ATM splice variant with a confirmed matching splice event was identified for this variant under the ATM PS1 splicing framework. Without a qualifying reference variant in the same splice motif and evidence that the predicted event matches, PS1 cannot be assigned.	cspec vcep_atm_ps1_1_5 clinvar
PS2	N/A	The ATM HBOP VCEP does not use PS2 for ATM variant interpretation.	cspec
PS3	Not assessed	No published or curated functional study for this exact variant was identified showing failure to rescue an ATM-specific functional readout or radiosensitivity. Available ATM functional supplementary tables reviewed for this case did not provide variant-specific evidence for PS3 assignment.	cspec vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	No case-control study or case series for this exact variant was identified showing statistically increased prevalence in affected individuals. The currently available evidence is insufficient to support PS4.	cspec clinvar
PM1	N/A	The ATM HBOP VCEP does not use PM1 because pathogenic and benign variants occur in the same regions and germline mutational hotspots are not well defined for ATM.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at AF 0.00465% (75/1,613,598 alleles) with grpmax FAF 0.005111%, which is above the ATM PM2_Supporting threshold of 0.001%. Because the observed population frequency exceeds the VCEP rarity cutoff, PM2 is not met.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No proband-level evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia. Therefore, no PM3 points can be assigned from the currently available evidence.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Under the ATM HBOP VCEP, PM4 is reserved for stop-loss variants. This intronic splice-region deletion is not a stop-loss variant.	cspec
PM5	Not met	For ATM, PM5_Supporting may be used for splice variants only when high-quality observed RNA evidence supports an NMD-prone splice defect meeting the truncation-cutoff framework. That level of RNA evidence is not available for this variant, so PM5 is not met.	cspec pm5_candidates
PM6	N/A	The ATM HBOP VCEP does not use PM6 for ATM variant interpretation.	cspec
PP1	Not assessed	No segregation data were identified for this variant. Without informative family observations, PP1 cannot be applied.	cspec
PP2	N/A	The ATM HBOP VCEP does not use PP2 because ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Met	SpliceAI predicts splice impact for this intronic donor-region deletion with a maximum delta score of 0.89, which is above the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions. This computational evidence supports an adverse splicing effect.	spliceai cspec
PP4	N/A	The ATM HBOP VCEP does not use PP4 for ATM variant interpretation.	cspec
PP5	N/A	PP5 is not used in the ATM HBOP VCEP framework.	cspec
BA1	Not met	This variant does not meet the ATM BA1 population threshold. The gnomAD v4.1 grpmax filtering allele frequency is 0.005111%, which is far below the BA1 threshold of greater than 0.5%.	gnomad_v4 cspec
BS1	Not met	This variant does not meet the ATM BS1 population threshold. The gnomAD v4.1 grpmax filtering allele frequency is 0.005111%, which is below the BS1 threshold of greater than 0.05%.	gnomad_v4 cspec
BS2	N/A	The ATM HBOP VCEP does not use BS2 for ATM variant interpretation.	cspec
BS3	Not assessed	No published or curated evidence was identified showing preserved splicing or preserved ATM function for this exact variant. Therefore, BS3 cannot be applied.	cspec vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	The ATM HBOP VCEP does not use BS4 for ATM variant interpretation.	cspec
BP1	N/A	The ATM HBOP VCEP does not use BP1 for ATM variant interpretation.	cspec
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected adult without ataxia-telangiectasia, and no qualifying co-occurrence evidence in cis was identified. Therefore, BP2 cannot be assigned.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM HBOP VCEP does not use BP3 for ATM variant interpretation.	cspec
BP4	Not met	SpliceAI predicts splice impact with a maximum delta score of 0.89, which is well above the ATM BP4 threshold of 0.1 for no predicted splice impact. Computational evidence therefore does not support BP4.	spliceai cspec
BP5	N/A	The ATM HBOP VCEP does not use BP5 for ATM variant interpretation.	cspec
BP6	N/A	BP6 is not used in the ATM HBOP VCEP framework.	cspec
BP7	N/A	This variant is an intronic donor-region deletion at +5 to +8 and does not fall into the ATM BP7 categories for synonymous variants, deep intronic variants beyond +7 or -21, or variants with observed normal RNA splicing. BP7 is therefore not applicable.	cspec

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