ATMc.2333A>GUncertain significance

Print report

Variant interpretation report

ATM c.2333A>G, p.(Asn778Ser)

NM_000051.4:c.2333A>G NP_000042.3:p.(Asn778Ser) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATM

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.5.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically and no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

14 / 1,613,972 alleles

gnomAD v4.1: 14 / 1,613,972 alleles. Recorded AF 8.67425e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.19346e-05; MAF= 0.00119%, 3/251370 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.63806e-05; MAF= 0.00264%, 3/113720 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 6 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 1

PM2 SupportingThe 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. Details ▾Hide ▴

Rule

Frequency ≤0.001% in gnomAD v4 dataset.

Evidence considered

gnomAD v4.1 AF 8.67425e-06 (0.000867%)
14/1
613
972 alleles
0 homozygotes.
gnomAD v4.1 grpmax FAF 6.15e-06.

Sources

gnomad_v4 ↗cspec ↗

Not met · 5 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Rule

Same amino acid change as a previously established pathogenic variant, with splicing ruled out for both variants.

Evidence considered

ATM PS1 guidance requires a previously established pathogenic reference variant with the same amino acid change.
Reviewed residue 778 entries in the ATM supplementary table did not identify a pathogenic same-amino-acid reference variant for N778S.

Still missing

A confirmed pathogenic reference variant encoding the same amino acid change would be needed for PS1.

Sources

cspec ↗vcep_a_t_m___p_s_1___1___5vcep_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 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. Details ▾Hide ▴

Rule

Case-control studies; p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.

Evidence considered

ClinVar shows mixed submissions with uncertain significance and likely benign assertions.
Literature screening did not identify qualifying ATM variant-specific PS4 statistics for c.2333A>G.

Still missing

A variant-specific case-control study meeting the ATM PS4 statistical threshold would be needed.

Sources

clinvar ↗PMID:20305132 ↗cspec ↗

PP3 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. Details ▾Hide ▴

Rule

Missense PP3 requires REVEL >0.7333.

Evidence considered

REVEL 0.099 for c.2333A>G / p.N778S.

Sources

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

BA1 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. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.5% in gnomAD v4 dataset.

Evidence considered

gnomAD v4.1 AF 8.67425e-06 (0.000867%)
14/1
613
972 alleles
0 homozygotes.

Sources

gnomad_v4 ↗cspec ↗

BS1 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. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.05% in gnomAD v4 dataset.

Evidence considered

gnomAD v4.1 grpmax FAF 6.15e-06 (0.000615%).

Sources

gnomad_v4 ↗cspec ↗

Not assessed · 6 · no assessment recorded

PS3 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. Details ▾Hide ▴

Rule

PS3 applies when a variant fails to rescue the required ATM-specific functional feature set.

Evidence considered

No reviewed ATM-specific functional source showed a qualifying abnormal rescue result for c.2333A>G / p.N778S.

Still missing

A clearly mapped ATM-specific abnormal functional assay result meeting the PS3 framework is needed.

Sources

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

PM3 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. Details ▾Hide ▴

Rule

PM3 uses the ATM PM3/BP2 point system.

Evidence considered

ATM VCEP requires point-based case evidence for PM3.

Still missing

Case-level genotype and phase data are needed for PM3 scoring under the ATM PM3/BP2 point system.

Sources

cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5

PP1 No segregation data were identified showing this variant segregating with a qualifying ATM-related recessive phenotype, so PP1 cannot be assessed. Details ▾Hide ▴

Rule

AR condition: segregation in affected relatives supports PP1 with increasing strength by family count.

Evidence considered

No segregation evidence was identified in the reviewed materials.

Still missing

Segregation data in informative families would be needed for PP1.

Remaining individuals1 / 62,486	1.6e-05
European (non-Finnish)13 / 1,180,046	1.1e-05