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.1 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%.2 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.3 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 PP3.4
Final classification
VUS
PM2
ATM
c.2333A>G
p.Asn778Ser
This variant
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.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically and no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
ATM c.2333A>G
PM2
→
VUS
3
vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1cspec ↗
4
vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1spliceai ↗cspec ↗
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.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 11 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
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 v4.1 AF 8.67425e-06 (0.000867%)14/1613
Assessed · not applied
· 5 not met · 6 not assessed
Pathogenic
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.
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.
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.
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.
PP1
No segregation data were identified showing this variant segregating with a qualifying ATM-related recessive phenotype, so PP1 cannot be assessed.
PP3
For missense variants, the ATM PP3 threshold requires REVEL greater than 0.7333.
Benign
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.
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.
BS3
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.
BP2
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.
BP4
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.
N/A · 16
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.67425e-06; MAF= 0.00087%, 14/1613972 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60036e-05; MAF= 0.00160%, 1/62486 alleles, homozygotes = 0); grpmax FAF= 6.15e-06.
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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00087%
· 14 / 1,613,972
0 hom · FAF 0.00062%
0 hom · FAF 0.00062%
Remaining individuals 1 / 62,486 |
0.0016% |
European (non-Finnish) 13 / 1,180,046 |
0.0011% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 251,370
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
European (non-Finnish) 3 / 113,720 |
0.0026% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (2 clinical laboratories).
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links