NM_000051.4:c.2222A>G

ATM · NP_000042.3:p.(Tyr741Cys) · NM_000051.4

GRCh37: chr11:108127039 A>G · GRCh38: chr11:108256312 A>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.(Tyr741Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.2222A>G (p.Tyr741Cys) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign submissions.

This variant is present in population databases at low frequency, including gnomAD v4.1 at 0.00217% overall (35/1,611,122 alleles) with a highest observed subpopulation frequency of 0.00447% in East Asian individuals, which is above the ATM PM2_Supporting threshold of <=0.001% and below the BS1 and BA1 thresholds.

Computational evidence is mixed: SpliceAI predicts possible splice impact with a maximum delta score of 0.29, supporting ATM PP3_Supporting, whereas REVEL is low at 0.153 and BayesDel is negative at -0.288378, which argues against a damaging missense effect but does not resolve the predicted splice concern.

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	N/A	This missense variant does not fall into the ATM PVS1 loss-of-function categories, and no RNA evidence was identified to show a null splicing consequence.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 was not applicable because no alternate single-nucleotide ATM variant producing the same Tyr741Cys amino acid change was identified, and the available missense evidence does not establish a same-amino-acid pathogenic reference variant.	cspec vcep_atm_ps1_1_5
PS2	N/A	PS2 is not applicable in the ATM VCEP specifications for this framework.	cspec
PS3	Not assessed	No validated ATM functional study was identified showing that this variant fails to rescue an ATM-specific cellular feature or radiosensitivity, so PS3 could not be applied.	cspec oncokb
PS4	Not assessed	This variant has been reported in ClinVar and once in COSMIC, but no case-control study or robust enrichment data in affected individuals were identified to support PS4.	clinvar cspec
PM1	N/A	PM1 is not applicable in the ATM VCEP specifications for this framework.	cspec
PM2	Not met	Population frequency does not meet the ATM PM2_Supporting threshold. In gnomAD v4.1 the overall allele frequency is 0.00217% (35/1,611,122) and the highest subpopulation frequency is 0.00447% in East Asian individuals, both above the <=0.001% threshold.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 could not be assessed.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	PM4 is not applicable because this variant is a missense substitution, not a stop-loss variant.	cspec
PM5	N/A	PM5 is not applicable because the ATM-specific PM5 rule is limited to truncating or qualifying splice variants upstream of p.Arg3047, and this variant is a missense substitution.	cspec
PM6	N/A	PM6 is not applicable in the ATM VCEP specifications for this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be applied.	cspec
PP2	N/A	PP2 is not applicable in the ATM VCEP specifications for this framework.	cspec
PP3	Met	SpliceAI predicts possible splice impact with a maximum delta score of 0.29, which is above the ATM PP3 splicing threshold of >=0.2 for missense variants. Although REVEL is low at 0.153 and BayesDel is negative at -0.288378, the ATM VCEP rule allows PP3_Supporting for predicted splice impact in missense variants, so PP3_Supporting is met with caution pending RNA confirmation.	cspec spliceai revel bayesdel
PP4	N/A	PP4 is not applicable in the ATM VCEP specifications for this framework.	cspec
PP5	N/A	PP5 is not applicable in the ATM VCEP specifications for this framework.	cspec
BA1	Not met	Population frequency is well below the ATM BA1 threshold. In gnomAD v4.1 the highest observed subpopulation frequency is 0.00447%, which is below the >0.5% threshold.	cspec gnomad_v4
BS1	Not met	Population frequency is below the ATM BS1 threshold. In gnomAD v4.1 the highest observed subpopulation frequency is 0.00447%, which is below the >0.05% threshold.	cspec gnomad_v4
BS2	N/A	BS2 is not applicable in the ATM VCEP specifications for this framework.	cspec
BS3	Not assessed	No validated ATM functional study was identified showing normal or rescued function for this variant, so BS3 could not be applied.	cspec oncokb
BS4	N/A	BS4 is not applicable in the ATM VCEP specifications for this framework.	cspec
BP1	N/A	BP1 is not applicable in the ATM VCEP specifications for this framework.	cspec
BP2	Not assessed	No evidence was identified that this variant co-occurs in trans with a pathogenic ATM variant in an unaffected individual, so BP2 could not be assessed.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is not applicable in the ATM VCEP specifications for this framework.	cspec
BP4	Not met	REVEL is low at 0.153 and BayesDel is negative at -0.288378, which would support a benign missense interpretation, but SpliceAI predicts possible splice impact with a maximum delta score of 0.29, above the ATM no-splice-impact threshold of <=0.1. Because the available computational evidence is conflicting and does not show a clearly benign overall effect, BP4 was not applied.	cspec revel bayesdel spliceai
BP5	N/A	BP5 is not applicable in the ATM VCEP specifications for this framework.	cspec
BP6	N/A	BP6 is not applicable in the ATM VCEP specifications for this framework.	cspec
BP7	N/A	BP7 is not applicable because this variant is a missense substitution rather than a synonymous or deep intronic variant.	cspec

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