NM_000051.4:c.2333A>G

ATM · NP_000042.3:p.(Asn778Ser) · NM_000051.4

GRCh37: chr11:108128290 A>G · GRCh38: chr11:108257563 A>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2_Supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asn778Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The ATM c.2333A>G (p.Asn778Ser; p.N778S) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with mixed germline classifications, including 8 submissions as uncertain significance and 2 as likely benign.

This variant is present in gnomAD v4.1 at 0.000867% (14/1,613,972 alleles; 0 homozygotes), and this is below the ATM PM2_Supporting threshold of less than or equal to 0.001%.

A high-confidence ATM supplementary functional table classified this variant as functional, but the reviewed ATM-specific materials did not provide a direct mapping of that result to BS3 or PS3 strength.

The REVEL score is 0.099, which is below the ATM PP3 threshold of greater than 0.7333 and within the BP4 missense range of less than or equal to 0.249, but no SpliceAI score was returned, so computational evidence was insufficient to apply BP4 and does not support PP3.

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
BP3	N/A	ATM-specific guidance states that BP3 should not be used for this gene, and this missense variant does not meet a permitted BP3 use case.	cspec
BP2	Not assessed	No co-occurrence or phase data were identified to show this variant in trans with a pathogenic ATM variant in an unaffected individual or in cis with another pathogenic variant, so BP2 cannot be assessed.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
BA1	Not met	The gnomAD v4.1 overall allele frequency is 0.000867% (14/1,613,972), which is below the ATM BA1 threshold of greater than 0.5%, so BA1 is not met.	gnomad_v4 cspec
PP4	N/A	ATM-specific guidance states that PP4 should not be used because the associated phenotypes are not sufficiently specific for this criterion as an independent line of evidence.	cspec
PM6	N/A	ATM-specific guidance states that PM6 should not be used for this gene.	cspec
PS4	Not met	This variant has been reported in ClinVar and in the literature, but no qualifying variant-specific case-control evidence was identified showing p-value less than or equal to 0.05 together with odds ratio, hazard ratio, or relative risk at least 2 or lower 95% confidence interval at least 1.5, so PS4 is not met.	clinvar PMID:20305132 cspec
BP6	N/A	ATM-specific guidance states that BP6 is not for use.	cspec
PM5	N/A	ATM-specific guidance limits PM5 to truncating or qualifying splice variants upstream of p.Arg3047 and states that PM5 should not be used for missense changes, so PM5 is not applicable to p.Asn778Ser.	cspec
PM1	N/A	ATM-specific guidance states that PM1 should not be used because benign and pathogenic variants occur in the same regions and germline mutational hotspots are not well defined.	cspec hotspots
PS2	N/A	ATM-specific guidance states that PS2 should not be used for this gene.	cspec
PS1	Not met	No previously established pathogenic ATM variant causing the same amino acid change was identified in the reviewed ATM-specific materials, so PS1 is not met.	cspec vcep_a_t_m___p_s_1___1___5 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
BP5	N/A	ATM-specific guidance states that BP5 should not be used for this gene.	cspec
PP3	Not met	For missense variants, the ATM PP3 threshold requires REVEL greater than 0.7333. This variant has REVEL 0.099, which is below that threshold, so PP3 is not met.	cspec 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
PP2	N/A	ATM-specific guidance states that PP2 should not be used because ATM does not have a defined low rate of benign missense variation.	cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia or another qualifying recessive presentation, so PM3 cannot be assessed.	cspec vcep_a_t_m___p_m_3___b_p_2___1___5
PM2	Met	The gnomAD v4.1 overall allele frequency is 0.000867% (14/1,613,972), which is below the ATM PM2_Supporting threshold of less than or equal to 0.001%, so PM2_Supporting is met.	gnomad_v4 cspec
PVS1	N/A	This is a missense variant, not a predicted loss-of-function variant. The variant-specific PVS1 assessment states that it does not fall into the default null-variant categories of nonsense, frameshift, or canonical plus or minus 1 or 2 splice variants, so PVS1 is not applicable.	cspec pvs1_gene_context pvs1_variant_assessment vcep_a_t_m___p_v_s_1___1___5
BP7	N/A	ATM-specific guidance limits BP7 to synonymous and deep intronic variants or qualifying RNA studies showing no splice defect. This variant is missense, so BP7 is not applicable.	cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 0.000615%, which is below the ATM BS1 threshold of greater than 0.05%, so BS1 is not met.	gnomad_v4 cspec
PM4	N/A	ATM-specific guidance limits PM4 to stop-loss variants. This missense variant does not meet that use case.	cspec
BP4	Not assessed	For ATM missense variants, BP4 requires REVEL less than or equal to 0.249 and no predicted splice impact with SpliceAI less than or equal to 0.1. The REVEL score is 0.099, which meets the missense threshold, but no SpliceAI score was returned, so BP4 cannot be fully assessed.	cspec spliceai 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
BP1	N/A	ATM-specific guidance states that BP1 should not be used for this gene.	cspec
BS4	N/A	ATM-specific guidance states that BS4 should not be used for this gene.	cspec
BS3	Not assessed	A high-confidence entry in an ATM supplementary functional table classified this variant as functional, but the reviewed ATM-specific materials did not provide a direct mapping from this result to the BS3 rescue-based strength framework, so BS3 was not applied.	cspec 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
BS2	N/A	ATM-specific guidance states that BS2 should not be used for this gene.	cspec
PP5	N/A	ATM-specific guidance states that PP5 is not for use.	cspec
PP1	Not assessed	No segregation data were identified showing this variant segregating with a qualifying ATM-related recessive phenotype, so PP1 cannot be assessed.	cspec
PS3	Not assessed	Although a supplementary functional table includes this variant, the reviewed ATM-specific materials did not provide a direct mapping showing that this variant failed to rescue the ATM-specific functional features required for PS3, so PS3 was not applied.	cspec 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

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.