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
ATM
Final classification
VUS
ATM c.2333A>G · p.Asn778Ser
ATM
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 ↗
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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