LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-15
Case ID: NM_000051.4_c.2207C_T_20260415_194108
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.2207C>T

ATM  · NP_000042.3:p.(Ala736Val)  · NM_000051.4
GRCh37: chr11:108127024 C>T  ·  GRCh38: chr11:108256297 C>T
Gene: ATM Transcript: NM_000051.4
Final call
PM2_Supporting BP4
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Ala736Val)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The ATM c.2207C>T (p.Ala736Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance by 4 clinical laboratories.
2
The variant is present at very low frequency in gnomAD, including 3 of 1458952 alleles in v4.1 with no homozygotes, which supports PM2_Supporting and is well below the ATM BS1 and BA1 frequency thresholds.
3
In silico evidence argues against a deleterious effect: REVEL is 0.103 and SpliceAI shows a maximum delta score of 0.02, supporting BP4 and arguing against PP3.
Final determination: The combination of one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4) results in uncertain significance due to conflicting evidence.
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 ATM PVS1 is for predicted loss-of-function variants using the ATM PVS1 decision tree. NM_000051.4:c.2207C>T is a missense variant, p.(Ala736Val), so PVS1 does not apply.
cspec prefetch
PS1 Not assessed No established pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified from the available sources, so PS1 was not applied.
cspec clinvar spliceai
PS2 N/A ATM VCEP marks PS2 as not applicable in this framework.
cspec
PS3 Not assessed No ATM-specific functional assay evidence showing failure to rescue an ATM-specific feature or radiosensitivity was identified for this variant, so PS3 was not applied.
cspec literature_pass
PS4 Not assessed No case-control evidence meeting the ATM VCEP PS4 threshold was identified, and the available ClinVar observation does not establish statistical enrichment in affected individuals.
cspec clinvar literature_pass
PM1 N/A ATM VCEP marks PM1 as not applicable in this framework.
cspec
PM2 Met The variant is present at extremely low frequency in gnomAD v4.1 (3/1,458,952 alleles; AF 2.05627e-06; no homozygotes), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%.
gnomad_v4 gnomad_v2 cspec
PM3 Not assessed No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in affected individuals under the ATM PM3/BP2 point system, so PM3 was not applied.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5
PM4 N/A ATM VCEP PM4 is specified for stop-loss variants. This variant is missense, p.(Ala736Val), so PM4 does not apply.
cspec prefetch
PM5 N/A ATM VCEP PM5 is specified for truncating or qualifying splice variants upstream of p.Arg3047. This variant is missense, so PM5 does not apply.
cspec prefetch
PM6 N/A ATM VCEP marks PM6 as not applicable in this framework.
cspec
PP1 Not assessed No segregation data were identified for this variant, so PP1 was not applied.
cspec literature_pass
PP2 N/A ATM VCEP marks PP2 as not applicable in this framework.
cspec
PP3 Not met The missense REVEL score is 0.103, which is well below the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact (max delta score 0.02), so PP3 is not met.
revel spliceai cspec
PP4 N/A ATM VCEP marks PP4 as not applicable in this framework.
cspec
PP5 N/A ATM VCEP marks PP5 as not applicable in this framework.
cspec
BA1 Not met The highest observed gnomAD v4.1 filtering allele frequency is far below the ATM VCEP BA1 threshold of >0.5%, so BA1 is not met.
gnomad_v4 cspec
BS1 Not met The gnomAD v4.1 frequency is far below the ATM VCEP BS1 threshold of >0.05%, so BS1 is not met.
gnomad_v4 cspec
BS2 N/A ATM VCEP marks BS2 as not applicable in this framework.
cspec
BS3 Not assessed No ATM-specific functional assay evidence showing rescue of an ATM-specific feature or radiosensitivity was identified for this variant, so BS3 was not applied.
cspec literature_pass
BS4 N/A ATM VCEP marks BS4 as not applicable in this framework.
cspec
BP1 N/A ATM VCEP marks BP1 as not applicable in this framework.
cspec
BP2 Not assessed No evidence was identified that this variant co-occurred in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual under the ATM PM3/BP2 point system, so BP2 was not applied.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5
BP3 N/A ATM VCEP marks BP3 as not applicable in this framework.
cspec
BP4 Met In silico evidence supports a benign interpretation: the REVEL score is 0.103, which is at or below the ATM VCEP BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a max delta score of 0.02, below the BP4 splicing threshold of ≤0.1.
revel spliceai cspec
BP5 N/A ATM VCEP marks BP5 as not applicable in this framework.
cspec
BP6 N/A ATM VCEP marks BP6 as not applicable in this framework.
cspec
BP7 N/A ATM VCEP BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect. This variant is missense, so BP7 does not apply.
cspec prefetch
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