NM_000051.3:c.4397_4398delinsCG

ATM · NP_000042.3:p.(Arg1466Pro) · NM_000051.3

GRCh37: chr11:108160489 GA>CG · GRCh38: chr11:108289762 GA>CG

Gene: ATM Transcript: NM_000051.3

Final call

VUS

PS3 supporting PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Arg1466Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.4397_4398delinsCG (p.Arg1466Pro) variant has been reported in ClinVar, where the overall expert-panel classification is uncertain significance and additional submissions range from uncertain significance to likely pathogenic and pathogenic.

This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM VCEP PM2_supporting population threshold of less than or equal to 0.001%.

In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence, supporting an abnormal ATM protein effect.

SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.01, and the equivalent c.4397G>C missense representation has a REVEL score of 0.677 in the ATM VCEP supplementary variant table, which is below the ATM PP3 threshold of greater than 0.7333 and above the BP4 threshold of less than or equal to 0.249.

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 met	This variant is represented at the protein level as p.(Arg1466Pro) and does not fall within the ATM VCEP null-variant categories for PVS1. SpliceAI predicts no significant splice impact with a max delta score of 0.01, so current evidence does not support a PVS1-based loss-of-function mechanism.	cspec pvs1_gene_context pvs1_variant_assessment spliceai vcep_atm_pvs1_1_5
PS1	Not met	This variant results in the missense change p.(Arg1466Pro). No different nucleotide change already established as pathogenic and producing the same amino acid substitution was identified, so PS1 is not met.	cspec clinvar vcep_atm_ps1_1_5
PS2	N/A	De novo evidence is not an applicable ATM VCEP criterion for this condition framework.	cspec
PS3	Met	In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence. Under ATM VCEP rules, functional evidence showing failure to rescue an ATM-specific feature supports PS3 at supporting strength, although assay-level confirmation for this specific entry should be completed during final review.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	This variant has been reported in ClinVar, but no case-control study or exact-variant enrichment data meeting the ATM VCEP PS4 threshold of p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, were identified. PS4 is not met.	cspec clinvar
PM1	N/A	PM1 is not applicable in the ATM VCEP framework because germline mutational hotspots and domains are not considered sufficiently specific for this code.	cspec
PM2	Met	This variant is absent from gnomAD v4.1, which is below the ATM VCEP PM2_supporting threshold of less than or equal to 0.001%. It is also absent from gnomAD v2.1, supporting rarity in population databases.	cspec gnomad_v4 gnomad_v2
PM3	Not met	No confirmed in trans observations with a pathogenic or likely pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 is not met.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	PM4 is reserved by the ATM VCEP for stop-loss variants and does not apply to this missense variant.	cspec
PM5	N/A	PM5 is not used for ATM missense variants in this framework. The ATM VCEP limits PM5 to truncating or qualifying splice variants upstream of p.Arg3047.	cspec
PM6	N/A	Assumed de novo evidence is not an applicable ATM VCEP criterion for this condition framework.	cspec
PP1	Not met	No segregation data were identified for this variant, so PP1 is not met.	cspec
PP2	N/A	PP2 is not applicable for ATM because missense variation is not sufficiently constrained to support this criterion.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the ATM splice PP3 threshold of at least 0.2. In the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is below the ATM missense PP3 threshold of greater than 0.7333. PP3 is not met.	cspec spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	PP4 is not applicable in the ATM VCEP framework.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1 and does not meet the ATM BA1 threshold of greater than 0.5% population frequency.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1 and does not meet the ATM BS1 threshold of greater than 0.05% population frequency.	cspec gnomad_v4
BS2	N/A	BS2 is not applicable for ATM because reduced penetrance limits interpretation of observations in healthy individuals.	cspec
BS3	Not met	No well-established study showing normal ATM function or rescue of radiosensitivity for this variant was identified. Available evidence does not support benign functional evidence, so BS3 is not met.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	BS4 is not applicable in the ATM VCEP framework.	cspec
BP1	N/A	BP1 is not applicable for ATM because pathogenic missense variants are known in this gene.	cspec
BP2	Not met	No qualifying co-occurrence evidence in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual was identified, so BP2 is not met.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is not applicable in the ATM VCEP framework.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is within the ATM BP4 splice range of less than or equal to 0.1. However, in the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is above the ATM BP4 missense threshold of less than or equal to 0.249. Because the missense prediction does not support a benign effect, BP4 is not met.	cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	BP5 is not applicable in the ATM VCEP framework.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	BP7 is reserved for synonymous and qualifying deep intronic variants and does not apply to this missense variant.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.