Variant classification summary

NM_000051.4:c.8362C>T

ATM · NP_000042.3:p.(His2788Tyr) · NM_000051.4

GRCh37: chr11:108214042 C>T · GRCh38: chr11:108343315 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2_Supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(His2788Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.8362C>T (p.His2788Tyr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 2 clinical laboratories.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, and the observed population frequency is therefore below the ATM PM2_Supporting threshold of <=0.001%.

3

A multiplex functional study classified p.His2788Tyr as non-functional with high confidence, but the available data are based on olaparib fitness assays and do not yet establish the ATM-specific rescue framework required to apply ATM PS3 or BS3 without manual review.

4

REVEL is 0.669, which is below the ATM PP3 threshold of >0.7333 and above the ATM BP4 missense threshold of <=0.249, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1.

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 is a missense variant, and it does not fall into the ATM PVS1 null-variant categories of nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or qualifying exon-level deletion variants.	cspec pvs1_gene_context pvs1_variant_assessment vcep_a_t_m___p_v_s_1___1___5
PS1	Not met	No pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified, so PS1 is not supported.	cspec clinvar vcep_a_t_m___p_s_1___1___5
PS2	N/A	PS2 is not used in the ATM VCEP framework.	cspec
PS3	Not assessed	A multiplex functional study classified p.(His2788Tyr) as non-functional with high confidence, but the available assay measures olaparib-related cell fitness and does not clearly demonstrate failure to rescue both an ATM-specific feature and radiosensitivity as required for ATM PS3.	cspec PMID:40580951 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
PS4	Not met	No case-control study or enrichment data showing a statistically significant excess of this variant in affected individuals were identified, so PS4 is not met.	cspec clinvar PMID:20050888 PMID:20301317 PMID:20301790 PMID:24418350 PMID:25394175 PMID:28492532 PMID:40580951
PM1	N/A	PM1 is not used in the ATM VCEP framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of <=0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 cannot be assessed.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
PM4	N/A	PM4 in the ATM VCEP framework is used for stop-loss variants, and this variant is a missense change.	cspec
PM5	N/A	ATM PM5 is restricted to qualifying truncating or splice variants upstream of p.Arg3047, and this variant is a missense substitution.	cspec
PM6	N/A	PM6 is not used in the ATM VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant in affected relatives, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not used in the ATM VCEP framework.	cspec
PP3	Not met	REVEL is 0.669, which is below the ATM PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the splicing threshold of >=0.2. These findings do not support PP3.	cspec spliceai
PP4	N/A	PP4 is not used in the ATM VCEP framework.	cspec
PP5	N/A	PP5 is not used in the ATM VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BA1 threshold of >0.5%.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BS1 threshold of >0.05%.	cspec gnomad_v4
BS2	N/A	BS2 is not used in the ATM VCEP framework.	cspec
BS3	Not assessed	No ATM VCEP-compatible benign functional evidence showing rescue of an ATM-specific feature or radiosensitivity was identified. The available multiplex study instead classified p.(His2788Tyr) as non-functional, so BS3 is not supported and requires no further benign functional weighting at this stage.	cspec PMID:40580951 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
BS4	N/A	BS4 is not used in the ATM VCEP framework.	cspec
BP1	N/A	BP1 is not used in the ATM VCEP framework.	cspec
BP2	Not assessed	No co-occurrence data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual, so BP2 cannot be assessed.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
BP3	N/A	BP3 is not used in the ATM VCEP framework.	cspec
BP4	Not met	REVEL is 0.669, which is above the ATM BP4 missense threshold of <=0.249, so benign missense prediction is not supported. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1, but this does not overcome the missense prediction result.	cspec spliceai
BP5	N/A	BP5 is not used in the ATM VCEP framework.	cspec
BP6	N/A	BP6 is not used in the ATM VCEP framework.	cspec
BP7	N/A	BP7 in the ATM VCEP framework is used for synonymous or deep intronic variants, and this variant is missense.	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.