Variant classification summary

NM_000051.4:c.6059G>T

ATM · NP_000042.3:p.(Gly2020Val) · NM_000051.4

GRCh37: chr11:108186602 G>T · GRCh38: chr11:108315875 G>T

Gene: ATM Transcript: NM_000051.4

Final call

PM2_Supporting PP3

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Gly2020Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.6059G>T (p.Gly2020Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance with multiple clinical laboratory submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4.

3

An ATM supplementary functional dataset classified this variant as non-functional, but the available evidence does not document the ATM VCEP-required rescue assay endpoints needed to apply PS3 or BS3.

4

In silico evidence supports a deleterious missense effect because REVEL is 0.753, which is above the ATM PP3 threshold of 0.7333, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.02.

Final determination: PM2_Supporting and PP3 are present, but this combination does not meet any ATM HBOP CSPEC/VCEP rule for Pathogenic, Likely Pathogenic, Likely Benign, or Benign classification; therefore this variant is classified as Uncertain Significance.

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 is a missense variant, and available evidence does not place it in the null-variant categories used for ATM PVS1. ATM-specific PVS1 guidance is therefore not applicable.	pvs1_gene_context pvs1_variant_assessment vcep_a_t_m___p_v_s_1___1___5 cspec
PS1	Not met	No pathogenic or likely pathogenic ATM variant producing the same amino acid change was identified, and SpliceAI does not suggest a splice effect that would support use of the ATM PS1 splicing table. Available evidence does not support PS1.	clinvar spliceai vcep_a_t_m___p_s_1___1___5 cspec
PS2	N/A	ATM-specific guidance lists PS2 as not applicable for this framework.	cspec
PS3	Not met	An ATM supplementary functional dataset listed this variant as non-functional, but the available evidence does not document the ATM VCEP-required rescue assay endpoints showing failure to rescue both an ATM-specific feature and radiosensitivity. The available data are therefore insufficient to apply PS3.	vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1 cspec
PS4	Not assessed	No case-control study or other quantitative enrichment data were identified showing this variant is significantly enriched in affected individuals. Available evidence does not support application of PS4 at this time.	literature_pass clinvar cspec
PM1	N/A	ATM-specific guidance lists PM1 as not applicable for this framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. A frequency of 0% is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, supporting PM2_Supporting.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia. Available evidence is insufficient to assign PM3 points.	clinvar vcep_a_t_m___p_m_3___b_p_2___1___5 cspec
PM4	N/A	This is not a stop-loss variant, so PM4 does not apply.	prefetch cspec
PM5	N/A	ATM-specific PM5 guidance applies to truncating or qualifying splice variants upstream of p.Arg3047, not to this missense substitution. PM5 is therefore not applicable.	prefetch cspec
PM6	N/A	ATM-specific guidance lists PM6 as not applicable for this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant in affected relatives, so PP1 cannot be assessed from the available evidence.	literature_pass cspec
PP2	N/A	ATM-specific guidance lists PP2 as not applicable for this framework.	cspec
PP3	Met	In silico evidence supports a deleterious effect for this missense variant because the REVEL score is 0.753, which is above the ATM PP3 threshold of >0.7333. SpliceAI predicts no meaningful splice effect with a max delta score of 0.02, supporting interpretation as a missense change rather than a splice-altering variant.	spliceai cspec revel
PP4	N/A	ATM-specific guidance lists PP4 as not applicable for this framework.	cspec
PP5	N/A	ATM-specific guidance lists PP5 as not applicable for this framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1. A frequency of 0% is below the ATM BA1 threshold of >0.5%, so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v4.1. A frequency of 0% is below the ATM BS1 threshold of >0.05%, so BS1 is not met.	gnomad_v4 cspec
BS2	N/A	ATM-specific guidance lists BS2 as not applicable for this framework.	cspec
BS3	Not met	No study was identified showing that this variant rescues an ATM-specific functional defect or radiosensitivity. The available supplementary functional dataset does not provide the ATM VCEP-required rescue assay evidence, so BS3 is not met.	vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1 cspec
BS4	N/A	ATM-specific guidance lists BS4 as not applicable for this framework.	cspec
BP1	N/A	ATM-specific guidance lists BP1 as not applicable for this framework.	cspec
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected individual or other setting that would qualify for BP2 points. Available evidence is insufficient to assess BP2.	clinvar vcep_a_t_m___p_m_3___b_p_2___1___5 cspec
BP3	N/A	ATM-specific guidance lists BP3 as not applicable for this framework.	cspec
BP4	Not met	Benign computational evidence is not supported because the REVEL score is 0.753, which is above the ATM BP4 missense threshold of ≤0.249. Although SpliceAI is low at 0.02 and does not predict splice disruption, the missense prediction does not support BP4.	spliceai cspec revel
BP5	N/A	ATM-specific guidance lists BP5 as not applicable for this framework.	cspec
BP6	N/A	ATM-specific guidance lists BP6 as not applicable for this framework.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or qualifying deep intronic variant, so BP7 does not apply.	prefetch cspec

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