NM_000051.3:c.8546G>C

ATM · NP_000042.3:p.(Arg2849Pro) · NM_000051.3

GRCh37: chr11:108216597 G>C · GRCh38: chr11:108345870 G>C

Gene: ATM Transcript: NM_000051.3

Final call

VUS

PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Arg2849Pro)

gnomAD AF

1.2393831342264328e-06 (v4.1)

ClinVar

Likely Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant (c.8546G>C, p.Arg2849Pro) in ATM is extremely rare in population databases, observed at an allele frequency of 0.00012% in gnomAD v4.1 (2/1,613,706 alleles), supporting PM2_Supporting under the ClinGen HBOP ATM VCEP v1.5.0 specifications.

The REVEL in silico predictor yields a score of 0.919, exceeding the VCEP PP3 threshold of >0.733, and SpliceAI predicts no splicing impact (max delta 0.01), supporting PP3 at supporting strength.

Exploratory functional evidence from high-throughput assays (PMID 31097817, PMID 29650054) suggests the variant impairs ATM kinase activity, which may support PS3. However, full-text verification of variant mention and confirmation that the assays meet VCEP-approved functional thresholds remain pending.

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has classified this variant as Likely Pathogenic (ClinVar variation ID 490737, review status: reviewed by expert panel). Seven clinical laboratories concur (6 Likely pathogenic, 1 Pathogenic).

Under the VCEP combination rules, the currently confirmed criteria (PM2_Supporting, PP3) yield 2 pathogenic supporting points, which is insufficient to reach Likely Pathogenic. The expert panel's LP classification likely incorporates additional evidence (PS3 functional data, PM3 trans observations, or PS1 comparator data) not fully verified in this automated adjudication.

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	This is a missense variant (p.Arg2849Pro); the ATM PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, or exon-level deletions). A missense substitution does not qualify for PVS1 assessment under the ClinGen HBOP ATM VCEP v1.5.0.	pvs1_variant_assessment
PS1	Not assessed	PS1 (same amino acid change as a previously established pathogenic variant regardless of nucleotide change) requires a known P/LP missense variant at Arg2849 with a different nucleotide change. No such comparator has been identified in ClinVar or the evidence packet. Splicing is ruled out for the variant under assessment (SpliceAI max delta 0.01), satisfying the VCEP prerequisite.	cspec pm5_candidates
PS2	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'	cspec
PS3	Not assessed	Exploratory evidence recovery identified functional data from PMID 31097817 (flow cytometry-based ATM kinase assay) and PMID 29650054 (saturation genome editing) reporting damaging effects for p.R2849P. However, full-text verification could not be completed (Sci-Hub landing pages only, no variant-specific text recovered). The VCEP requires specific functional assay types (ATM-specific feature phosphorylation ± radiosensitivity rescue) and curator judgment of assay quality. Cannot assign PS3 without confirming variant mention and assay alignment with VCEP-approved thresholds.
PS4	Not met	No case-control study with variant-level odds ratio or relative risk has been identified in the clinical literature. The VCEP requires p≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5). Proband counting is not used per VCEP (PS4_Moderate: 'Do not use').	cspec
PS5	N/A	PS5 is not included in the ClinGen HBOP ATM VCEP v1.5.0 specification. The VCEP does not recognize this criterion for ATM variant classification.	cspec
PM1	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.'	cspec
PM2	Met	This variant is extremely rare in population databases. In gnomAD v4.1, it is observed at an overall allele frequency of 0.00012% (2/1,613,706 alleles, 0 homozygotes), which is well below the VCEP PM2_Supporting threshold of ≤0.001%. It is absent from gnomAD v2.1. The highest subpopulation frequency is in Remaining individuals at 0.00160% (1/62,468). PM2_Supporting applies.	gnomad_v4
PM5	N/A	Per ClinGen HBOP 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 meeting specific PVS1_VS(RNA) criteria. This is a missense variant (p.Arg2849Pro); the VCEP explicitly states 'Do not use for missense changes.'	cspec pm5_candidates
PM6	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'	cspec
PP1	Not met	No segregation data has been identified for this variant. The VCEP allows PP1 for AR conditions (ataxia-telangiectasia) requiring both variants identified in affected relatives, but no family studies with c.8546G>C segregation have been found.	cspec
PP2	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use: ATM does not have a defined low rate of missense benign variation.'	cspec
PP3	Met	REVEL score is 0.919, exceeding the VCEP PP3 threshold of >0.733 for missense variants. SpliceAI confirms no confounding splice impact (max delta score 0.01). PP3 applies at supporting strength.	revel spliceai
PP4	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology... Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3/BP2 table.'	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	The overall allele frequency in gnomAD v4.1 is 0.00012%, far below the VCEP BA1 stand-alone threshold of Grpmax Filtering AF >0.5%. This variant does not meet BA1.	gnomad_v4 cspec
BS1	Not met	The overall allele frequency in gnomAD v4.1 is 0.00012%, below the VCEP BS1 strong benign threshold of Grpmax Filtering AF >0.05%. This variant does not meet BS1.	gnomad_v4 cspec
BS2	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use: ATM has incomplete penetrance.'	cspec
BS3	Not met	Available functional evidence (exploratory findings from PMID 31097817 and PMID 29650054) indicates a damaging effect on ATM function rather than rescue of ATM-specific features. No assay demonstrates wild-type-like activity or rescue of ATM-specific phosphorylation targets or radiosensitivity. BS3 criteria (benign functional evidence) are not supported.	cspec
BS4	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results. AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time.'	cspec
BP1	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use: Missense pathogenic variants are known for ATM.'	cspec
BP2	Not met	No evidence has been identified of this variant observed in trans with a known pathogenic ATM variant in an unaffected individual aged 18 years or older. The exploratory search found no phased co-occurrence data. BP2 is not supported.	cspec
BP4	Not met	REVEL score is 0.919, which exceeds the VCEP BP4 threshold of ≤0.249 for missense variants. SpliceAI shows no splicing impact (max delta 0.01, ≤0.1), but the missense computational prediction is strongly deleterious. BP4 is not supported.	revel spliceai cspec
BP5	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype... ATM has low penetrance and will naturally occur with other pathogenic variants more frequently.'	cspec
BP6	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	N/A	The main BP7 rule applies only to synonymous and deep intronic variants (beyond +7 donor / -21 acceptor). This is a missense variant (c.8546G>C, p.Arg2849Pro) and does not qualify. BP7_RNA (observed lack of aberrant RNA defect) could theoretically apply but no RNA functional data is available for this variant.	cspec
BP3	N/A	Per ClinGen HBOP ATM VCEP v1.5.0: 'Do not use.' BP3 applies to in-frame deletions/insertions in a repetitive region without known function; this variant is a single nucleotide substitution.	cspec
PM3	N/A	Per user instruction, PM3 is trivially not applicable for this adjudication. No evidence of the variant in trans with a pathogenic ATM variant causing ataxia-telangiectasia was identified, and PM3/BP2 trans observations require proband-level data not available in the evidence packet.	cspec
PM4	N/A	Per ClinGen HBOP ATM VCEP v1.5.0, PM4 is used for stop-loss variants only. This is a missense substitution (c.8546G>C, p.Arg2849Pro), not a stop-loss variant.	cspec

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