Variant classification summary

NM_000051.4:c.4247A>G

ATM · NP_000042.3:p.(Gln1416Arg) · NM_000051.4

GRCh37: chr11:108160339 A>G · GRCh38: chr11:108289612 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.(Gln1416Arg)

gnomAD AF

8.72346974763002e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.4247A>G (p.Gln1416Arg) is a rare missense variant in ATM with an allele frequency of 0.00087% in gnomAD v4.1 (14/1,604,866 alleles, 0 homozygotes), meeting PM2_Supporting under the ClinGen HBOP VCEP v1.5.0 threshold of ≤0.001%.

2

Computational predictors are inconclusive: REVEL score of 0.45 falls between the VCEP thresholds for PP3 (>0.7333) and BP4 (≤0.249), and BayesDel score of -0.0913068 is weakly benign. SpliceAI predicts no splicing impact (max delta=0.04). Neither PP3 nor BP4 is met.

3

This variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories (ClinVar Variation ID: 230064, review status: criteria provided, single submitter). No expert panel classification has been recorded.

4

No variant-specific functional data (PS3/BS3), case-control studies (PS4), segregation data (PP1), or co-occurrence data (BP2) were identified for this variant. OncoKB reports Unknown Oncogenic Effect. The variant has not been reported in COSMIC.

5

With only PM2_Supporting met and no pathogenic moderate/strong/very strong criteria fulfilled, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP framework as specified by the ClinGen HBOP VCEP for ATM v1.5.0.

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
PVS1	N/A	PVS1 is not applicable: NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg), which does not fall into the null-variant categories (nonsense, frameshift, canonical +/-1,2 splice sites) required for PVS1 under the ATM VCEP v1.5.0 decision tree.	cspec vcep_atm_pvs1_1_5 pvs1_generic_framework
PS1	Not met	PS1 requires a known (likely) pathogenic missense variant at the same nucleotide position with the same predicted amino acid change and splicing ruled out for both. No such comparator variant was identified at this codon in ClinVar or the available literature. No evidence to support PS1.	cspec vcep_atm_ps1_1_5 clinvar
PS2	N/A	PS2 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
PS3	Not assessed	No variant-specific functional assay data were identified for NM_000051.4:c.4247A>G (p.Gln1416Arg). OncoKB reports Unknown Oncogenic Effect; no publications with direct functional characterization of this variant were found. Under ATM VCEP v1.5.0, PS3 requires demonstration that the variant fails to rescue ATM-specific features (e.g., phosphorylation of ATM targets) and/or radiosensitivity.	cspec oncokb
PS4	Not assessed	No variant-specific case-control study with adequate statistical power was identified for NM_000051.4:c.4247A>G. The large-scale ATM studies identified (e.g., PMID:33471991, Dorling et al. 2021) focused on protein-truncating variants and did not provide variant-level data for this missense change. Under ATM VCEP v1.5.0, PS4 requires case-control studies with p-value ≤0.05 and OR ≥2 or lower 95% CI ≥1.5.	cspec
PS5	N/A	PS5 is not defined in the ATM VCEP v1.5.0 criteria set and is not applicable under this framework.	cspec
PM1	N/A	PM1 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
PM2	Met	This variant is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 8.72e-06 (0.00087%; 14/1,604,866 alleles, 0 homozygotes) with grpmax filtering AF of 6.17e-06 (0.000617%). This is well below the ATM VCEP v1.5.0 PM2_Supporting threshold of ≤0.001% in gnomAD v4. The variant is also rare in gnomAD v2.1 (AF=1.63e-05; 4/245,772 alleles).	gnomad_v2 gnomad_v4 cspec
PM5	N/A	Under ATM VCEP v1.5.0, PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA) applied. NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg) and does not meet these criteria. No same-residue missense comparators were identified via the PM5 candidate search.	cspec vcep_atm_pm3_bp2_1_5
PM6	N/A	PM6 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
PP1	Not assessed	No segregation data were identified for NM_000051.4:c.4247A>G. Under ATM VCEP v1.5.0, PP1 is applied under an autosomal recessive model (Ataxia Telangiectasia) with segregation in affected relatives. No family studies with this variant were found.	cspec
PP2	N/A	PP2 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
PP3	Not met	Under ATM VCEP v1.5.0, PP3 for missense variants requires a REVEL score >0.7333. The REVEL score for p.Gln1416Arg is 0.45, which falls below this threshold. SpliceAI predicts no significant splicing impact (max delta = 0.04), so the splicing PP3 pathway (SpliceAI ≥0.2) does not apply. The BayesDel score is -0.0913068, which is not strongly damaging.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
PP5	N/A	PP5 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BA1	Not met	Under ATM VCEP v1.5.0, BA1 requires a grpmax filtering AF >0.5% in gnomAD v4. The observed grpmax FAF is 6.17e-06 (0.000617%), far below this threshold. The variant is extremely rare, not common.	gnomad_v4 cspec
BS1	Not met	Under ATM VCEP v1.5.0, BS1 requires a grpmax filtering AF >0.05% in gnomAD v4. The observed grpmax FAF is 6.17e-06 (0.000617%), far below this threshold.	gnomad_v4 cspec
BS2	N/A	BS2 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BS3	Not assessed	No variant-specific functional rescue data were identified for NM_000051.4:c.4247A>G (p.Gln1416Arg). Under ATM VCEP v1.5.0, BS3 requires demonstration that the variant rescues ATM-specific features and/or radiosensitivity. No such studies were found.	cspec
BS4	N/A	BS4 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BP1	N/A	BP1 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BP2	Not assessed	No co-occurrence (in trans with a pathogenic ATM variant) data were identified for NM_000051.4:c.4247A>G. Under ATM VCEP v1.5.0, BP2 assigns negative points per proband when the variant co-occurs in trans with a known pathogenic variant in an Ataxia Telangiectasia proband. No such observations were found in the available evidence.	cspec vcep_atm_pm3_bp2_1_5
BP4	Not met	Under ATM VCEP v1.5.0, BP4 for missense variants requires a REVEL score ≤0.249. The REVEL score for p.Gln1416Arg is 0.45, which exceeds this threshold. While SpliceAI predicts no splicing impact (max delta=0.04), the splicing BP4 pathway applies specifically to splicing variants, not this missense. The BayesDel score of -0.0913068 is weakly in the benign direction but does not override the VCEP-specific REVEL threshold.	cspec revel bayesdel spliceai
BP5	N/A	BP5 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BP6	N/A	BP6 is listed as Not Applicable by the ATM VCEP v1.5.0.	cspec
BP7	N/A	Under ATM VCEP v1.5.0, BP7 applies only to synonymous (silent) substitutions and deep intronic variants. NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg) and does not qualify.	cspec

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