NM_000051.4:c.2930G>A

ATM · NP_000042.3:p.(Cys977Tyr) · NM_000051.4

GRCh37: chr11:108141986 G>A · GRCh38: chr11:108271259 G>A

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Cys977Tyr)

gnomAD AF

2.4854569699048445e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.2930G>A (p.Cys977Tyr; p.C977Y) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic, although at least one submission classifies it as uncertain significance.

This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 0.00025% (4/1,609,362 alleles) and gnomAD v2.1 showing 0.00340% (1/29,448 alleles), which is below the ATM PM2_Supporting threshold of 0.001%.

Computational evidence supports a damaging missense effect, with REVEL 0.778 above the ATM PP3 threshold of 0.7333 and BayesDel 0.318994, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.02.

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 is a missense variant, not a predicted null variant, and the ATM PVS1 framework is intended for loss-of-function events. SpliceAI predicts no significant splice impact for this variant (max delta score 0.02), so the available evidence does not support applying PVS1.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	ATM PS1 can be used for a missense change when a different nucleotide change is already established as pathogenic or likely pathogenic for the same amino acid substitution and splicing is ruled out. SpliceAI for this variant is low (max delta score 0.02), but no qualifying same-amino-acid pathogenic comparator was identified in the available evidence, so PS1 was not assessed.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	The ATM VCEP specification designates PS2 as not applicable for this framework.	cspec
PS3	Not assessed	ATM PS3 requires variant-specific functional studies showing failure to rescue an ATM-specific feature, with stronger weight requiring failure to rescue both an ATM-specific feature and radiosensitivity. No qualifying variant-specific functional assay evidence was identified for this variant in the available curated sources, so PS3 was not assessed.	cspec oncokb clinvar
PS4	Not assessed	ATM PS4 requires case-control evidence with p-value 0.05 or less and effect size at least 2. No qualifying case-control or enrichment data for this exact variant were identified in the available evidence, so PS4 was not assessed.	cspec clinvar
PM1	N/A	The ATM VCEP specification designates PM1 as not applicable for this framework.	cspec
PM2	Met	This variant is very rare in population databases. In gnomAD v4.1 the total allele frequency is 0.00025% (4/1,609,362 alleles) and the highest observed subpopulation frequency is 0.00034%, both below the ATM PM2_Supporting threshold of 0.001%.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	ATM PM3 requires observations in trans with a pathogenic variant in individuals with ataxia-telangiectasia and scoring by the ATM PM3/BP2 point framework. No qualifying trans observations or point-based evidence were identified for this variant, so PM3 was not assessed.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	ATM applies PM4 to stop-loss variants. This is a missense variant, so PM4 is not applicable.	cspec
PM5	N/A	For ATM, PM5 is a gene-specific truncation or splice-related rule rather than a classic same-residue missense rule. This missense variant does not fit the ATM PM5 rule, so PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	The ATM VCEP specification designates PM6 as not applicable for this framework.	cspec
PP1	Not assessed	ATM PP1 in this framework requires segregation in affected relatives for the recessive ataxia-telangiectasia phenotype. No segregation data were identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	The ATM VCEP specification designates PP2 as not applicable for this framework.	cspec
PP3	Met	Computational evidence supports a deleterious missense effect. The REVEL score is 0.778, which is above the ATM PP3 threshold of 0.7333, and BayesDel is 0.318994. SpliceAI predicts no significant splice impact (max delta score 0.02), so the supporting computational evidence is for missense effect rather than splice disruption.	cspec revel bayesdel spliceai
PP4	N/A	The ATM VCEP specification designates PP4 as not applicable for this framework.	cspec
PP5	N/A	The ATM VCEP specification designates PP5 as not applicable for this framework.	cspec
BA1	Not met	This variant does not meet the ATM BA1 threshold. In gnomAD v4.1 the highest observed population frequency is 0.00034%, which is far below the BA1 threshold of more than 0.5%.	cspec gnomad_v4
BS1	Not met	This variant does not meet the ATM BS1 threshold. In gnomAD v4.1 the highest observed population frequency is 0.00034%, which is far below the BS1 threshold of more than 0.05%.	cspec gnomad_v4
BS2	N/A	The ATM VCEP specification designates BS2 as not applicable for this framework.	cspec
BS3	Not assessed	ATM BS3 requires variant-specific functional studies showing rescue of both an ATM-specific feature and radiosensitivity for moderate weight, or rescue of either for supporting weight. No qualifying benign functional rescue evidence was identified for this variant, so BS3 was not assessed.	cspec oncokb clinvar
BS4	N/A	The ATM VCEP specification designates BS4 as not applicable for this framework.	cspec
BP1	N/A	The ATM VCEP specification designates BP1 as not applicable for this framework.	cspec
BP2	Not assessed	ATM BP2 requires co-occurrence or homozygosity evidence scored through the ATM PM3/BP2 framework in unaffected or non-ataxia-telangiectasia settings. No qualifying benign co-occurrence evidence was identified for this variant, so BP2 was not assessed.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM VCEP specification designates BP3 as not applicable for this framework.	cspec
BP4	Not met	Benign computational evidence is not supported. Although SpliceAI predicts no significant splice impact (max delta score 0.02, below the BP4 splice threshold of 0.1), the REVEL score is 0.778, which is well above the BP4 missense threshold of 0.249 and instead supports PP3.	cspec revel spliceai
BP5	N/A	The ATM VCEP specification designates BP5 as not applicable for this framework.	cspec
BP6	N/A	The ATM VCEP specification designates BP6 as not applicable for this framework.	cspec
BP7	N/A	ATM BP7 is intended for synonymous or deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This is a missense variant, so BP7 is not applicable.	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.