Variant classification summary

NM_000051.3:c.8174A>G

ATM · NP_000042.3:p.(Asp2725Gly) · NM_000051.3

GRCh37: chr11:108206594 A>G · GRCh38: chr11:108335867 A>G

Gene: ATM Transcript: NM_000051.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Asp2725Gly)

gnomAD AF

3.717564251902154e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.3:c.8174A>G (p.Asp2725Gly) in ATM is a rare missense variant observed in gnomAD v4.1 at a frequency of 0.00037% (6/1,613,960 alleles), meeting ATM VCEP PM2_Supporting.

2

In silico prediction tools consistently suggest a deleterious effect: REVEL score of 0.968 exceeds the ATM VCEP PP3_Supporting threshold of >0.7333, and the ClinGen HBOP VCEP supplemental table classifies this variant as Non-functional with Medium-high confidence based on combined computational scores.

3

No functional studies, segregation data, case-control analyses, or trans-observation data are available for this variant. The variant has not been reported as pathogenic by any reputable source.

4

With PM2_Supporting and PP3_Supporting as the only met criteria, this variant does not reach the threshold for Likely Pathogenic or Likely Benign under the ClinGen HBOP VCEP v1.5.0 combination rules. The classification is Uncertain Significance.

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	NM_000051.3:c.8174A>G is a missense variant (p.Asp2725Gly) and does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ATM VCEP PVS1 decision tree is not triggered.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No known pathogenic or likely pathogenic variant has been established at the same nucleotide position (c.8174). The ATM VCEP PS1 rule for missense changes requires a P or LP reference variant at the same residue with splicing ruled out for both. c.8174A>T (D2725V) is present in ClinVar as Uncertain significance and classified as Non-functional by the VCEP supplement table, thus does not serve as a P/LP comparator.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	ClinGen HBOP VCEP Version 1.5.0 lists PS2 as Not Applicable.	cspec
PS3	Not assessed	No variant-specific functional assay data have been reported for NM_000051.3:c.8174A>G. The ATM VCEP supplemental table (PMID:40580951) classifies this variant as Non-functional based on computational predictions (boostDM, EVE, REVEL, AlphaMissense), not experimental functional evidence. Color Health ClinVar submission (SCV000913075) explicitly states functional studies have not been reported for this variant.	clinvar vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control study has been identified that provides variant-specific odds ratio, relative risk, or p-value for NM_000051.3:c.8174A>G. The ATM VCEP requires p ≤ 0.05 AND (OR/HR/RR ≥ 2 OR lower 95% CI ≥ 1.5). The variant is absent from all reviewed publications at the variant level.	clinvar
PS5	Not met	No reputable source has reported NM_000051.3:c.8174A>G as pathogenic. ClinVar lists this variant as Uncertain significance from three clinical laboratories. Under generic ACMG/AMP rules, PS5 requires a reputable source to report the variant as pathogenic with evidence unavailable for independent evaluation, which is not satisfied.	clinvar
PM1	N/A	ClinGen HBOP VCEP Version 1.5.0 lists PM1 as Not Applicable.	cspec
PM2	Met	The variant frequency in gnomAD v4.1 (AF=0.00037%, 6/1,613,960 alleles; grpmax FAF=0.00018%) is ≤0.001% per the ATM VCEP PM2 rule. The variant is absent from gnomAD v2.1 and gnomAD-Canada. At 0.00037%, this meets the VCEP PM2_Supporting threshold.	gnomad_v4
PM5	N/A	The ATM VCEP PM5 rule applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants meeting specific criteria. NM_000051.3:c.8174A>G is a missense variant (p.Asp2725Gly) and does not meet the VCEP PM5 structural requirements.	cspec pm5_candidates
PM6	N/A	ClinGen HBOP VCEP Version 1.5.0 lists PM6 as Not Applicable.	cspec
PP1	Not assessed	No segregation data are available for NM_000051.3:c.8174A>G. ATM-associated ataxia-telangiectasia is an autosomal recessive condition; the VCEP PP1 rule requires segregation in affected relatives. No family studies or cosegregation data involving this variant were identified in any reviewed source.
PP2	N/A	ClinGen HBOP VCEP Version 1.5.0 lists PP2 as Not Applicable.	cspec
PP3	Met	REVEL score of 0.968 exceeds the ATM VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no significant splice impact (max delta=0.07). The VCEP supplemental table (PMID:40580951) independently classifies this variant as Non-functional based on a combined computational score integrating boostDM, EVE, REVEL, and AlphaMissense, consistent with a deleterious in silico prediction.	revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	ClinGen HBOP VCEP Version 1.5.0 lists PP4 as Not Applicable.	cspec
PP5	Not met	No reputable source has reported NM_000051.3:c.8174A>G as pathogenic. The ClinGen HBOP VCEP lists PP5 as Not Applicable. Under generic ACMG/AMP, PP5 requires a reputable source to have recently reported the variant as pathogenic, which has not occurred for this variant.	clinvar
BA1	Not met	The grpmax filtering allele frequency in gnomAD v4.1 is 0.00018% (FAF=1.83e-06), which is well below the ATM VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Not met	The grpmax filtering allele frequency in gnomAD v4.1 is 0.00018% (FAF=1.83e-06), which is below the ATM VCEP BS1 threshold of >0.05%.	gnomad_v4
BS2	N/A	ClinGen HBOP VCEP Version 1.5.0 lists BS2 as Not Applicable.	cspec
BS3	Not assessed	No experimental functional studies demonstrating rescue of ATM function have been reported for NM_000051.3:c.8174A>G. The ATM VCEP BS3 rules require variant-specific experimental evidence showing rescue of ATM-specific features and/or radiosensitivity. No such data are available.	clinvar
BS4	N/A	ClinGen HBOP VCEP Version 1.5.0 lists BS4 as Not Applicable.	cspec
BP1	N/A	ClinGen HBOP VCEP Version 1.5.0 lists BP1 as Not Applicable.	cspec
BP2	Not assessed	No observations of NM_000051.3:c.8174A>G in trans with a pathogenic ATM variant in an unaffected individual were identified. The ATM VCEP BP2 rule requires co-occurrence data in unaffected (non-A-T) individuals, which were not found.
BP4	Not met	REVEL score of 0.968 exceeds the ATM VCEP BP4 missense threshold of ≤0.249. Multiple in silico predictors (REVEL 0.968, AlphaMissense 0.9984, BayesDel 0.482, boostDM 0.646, EVE 0.801) consistently suggest a deleterious effect. SpliceAI max delta score is 0.07, which is ≤0.1 for the splicing component of BP4, but this missense variant is assessed under the REVEL rule.	revel bayesdel spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	ClinGen HBOP VCEP Version 1.5.0 lists BP5 as Not Applicable.	cspec
BP6	N/A	ClinGen HBOP VCEP Version 1.5.0 lists BP6 as Not Applicable.	cspec
BP7	N/A	NM_000051.3:c.8174A>G is a missense variant (p.Asp2725Gly). The ATM VCEP BP7 rule applies to synonymous and deep intronic variants, not missense substitutions. No RNA-level evidence of normal splicing is available for BP7(RNA) consideration.	cspec

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