NM_000051.4:c.7835G>A

ATM · NP_000042.3:p.(Arg2612Lys) · NM_000051.4

GRCh37: chr11:108203535 G>A · GRCh38: chr11:108332808 G>A

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP4 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2612Lys)

gnomAD AF

3.987686025553092e-06 (v2.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.7835G>A (p.Arg2612Lys) is a missense variant in ATM, a gene where loss of function is an established mechanism for ataxia telangiectasia (autosomal recessive) and ATM-related cancer predisposition (autosomal dominant). The variant is absent from gnomAD v4.1 and present at extremely low frequency in gnomAD v2.1 (1/250,772 alleles, NFE only).

PM2_Supporting is met: the variant frequency (absent from gnomAD v4.1) satisfies the VCEP threshold of ≤0.001%.

BP4_Supporting is met: REVEL score of 0.086 is ≤0.249, SpliceAI max delta of 0.0 is ≤0.1, and BayesDel score of −0.523 is in the benign range. Multiple computational tools consistently predict a neutral effect.

No functional data (PS3/BS3), segregation data (PP1), case-control data (PS4), or variant-specific publications were identified for this variant. OncoKB reports unknown oncogenic effect, and the VCEP supplementary functional tables do not include p.Arg2612Lys.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories and as Likely benign by one clinical laboratory (Variation ID 407542). No expert panel classification is available.

Under the ClinGen HBOP ATM VCEP v1.5 combination rules, PM2_Supporting (1 pathogenic supporting) and BP4_Supporting (1 benign supporting) together trigger Rule 31: Uncertain Significance — Conflicting Evidence.

Final determination: Rule31 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - 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	NM_000051.4:c.7835G>A is a missense variant (p.Arg2612Lys), not a null variant (nonsense, frameshift, or canonical splice site). The ATM VCEP PVS1 decision tree applies only to null variant types; missense variants are not eligible for PVS1.	pvs1_generic_framework vcep_atm_pvs1_1_5
PS1	Not met	No evidence that the same amino acid change (p.Arg2612Lys) produced by a different nucleotide substitution has been classified as pathogenic or likely pathogenic. PS1 requires a known pathogenic comparator with the identical amino acid change via a different nucleotide change, and no such comparator variant is documented in the case materials.	clinvar cspec
PS2	N/A	ATM VCEP v1.5 does not permit use of PS2: '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 met	No functional data available for NM_000051.4:c.7835G>A (p.Arg2612Lys). OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. The VCEP supplementary functional tables (Suppl_TableS1, clingen_hbop_atm kinase activity and radiosensitivity tables) do not include this variant. No publications characterizing the functional impact of this variant were identified.	oncokb vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	No case-control studies or affected individual case reports featuring NM_000051.4:c.7835G>A were identified. The VCEP PS4 rule requires case-control data with p≤0.05 AND (OR≥2 or lower 95% CI ≥1.5), which is not available for this variant.	clinvar cspec
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework. The recognized pathogenic criteria are PVS1, PS1, PS2, PS3, PS4, PM1, PM2, PM3, PM4, PM5, PM6, PP1, PP2, PP3, PP4, and PP5.
PM1	N/A	ATM VCEP v1.5 does not permit use of PM1: '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 absent from gnomAD v4.1. Under the ATM VCEP PM2 rule, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. In gnomAD v2.1, the variant is present at extremely low frequency (AF=3.99×10⁻⁶; 1/250,772 alleles, NFE subpopulation only, no homozygotes).	gnomad_v2 gnomad_v4 cspec
PM5	N/A	ATM VCEP restricts PM5 to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants where PVS1_VS(RNA) is applied. Missense changes are explicitly excluded: 'Do not use for missense changes: Multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them.'	cspec pm5_candidates
PM6	N/A	ATM VCEP v1.5 does not permit use of PM6: '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 are available for this variant. The VCEP permits PP1 for AR conditions (ataxia telangiectasia) when segregation in affected relatives is demonstrated, but no such data exist in the case materials.
PP2	N/A	ATM VCEP v1.5 does not permit use of PP2: 'Do not use: ATM does not have a defined low rate of missense benign variation.'	cspec
PP3	Not met	REVEL score is 0.086, which is well below the VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.0). Computational evidence does not support a deleterious effect.	revel spliceai bayesdel cspec
PP4	N/A	ATM VCEP v1.5 does not permit use of PP4: '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	N/A	ATM VCEP v1.5 does not permit use of PP5: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' — not an expert panel classification that would trigger PP5 even under generic override rules.	cspec clinvar
BA1	Not met	The variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires Grpmax Filtering AF > 0.5% in gnomAD v4, which is not met. The variant is extremely rare, appearing in only 1/250,772 alleles in gnomAD v2.1.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires Grpmax Filtering AF > 0.05% in gnomAD v4, which is not met.	gnomad_v2 gnomad_v4 cspec
BS2	N/A	ATM VCEP v1.5 does not permit use of BS2: 'Do not use: ATM has incomplete penetrance.'	cspec
BS3	Not met	No functional data demonstrating a benign effect for NM_000051.4:c.7835G>A (p.Arg2612Lys) are available. The VCEP supplementary functional tables do not include this variant, and no publications were identified that assayed its functional impact.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	ATM VCEP v1.5 does not permit use of BS4: '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.'	cspec
BP1	N/A	ATM VCEP v1.5 does not permit use of BP1: 'Do not use: Missense pathogenic variants are known for ATM.'	cspec
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged 18 years or older. The VCEP BP2 point system requires specific proband data that are not available in the case materials.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	REVEL score is 0.086, which is ≤0.249 (VCEP BP4 threshold for missense variants). SpliceAI predicts no splicing impact (max delta = 0.0, which is ≤0.1). BayesDel score is −0.523 (predicted benign). Multiple independent computational tools consistently predict a neutral effect on the gene product.	revel spliceai bayesdel cspec
BP5	N/A	ATM VCEP v1.5 does not permit use of BP5: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.'	cspec
BP6	N/A	ATM VCEP v1.5 does not permit use of BP6: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' — not an expert panel benign classification.	cspec clinvar
BP7	N/A	BP7 under the ATM VCEP is applicable only to synonymous and deep intronic variants. NM_000051.4:c.7835G>A is a missense variant (p.Arg2612Lys) and does not qualify for BP7.	cspec
BP3	N/A	Skipped per user instruction. ATM VCEP v1.5 also marks BP3 as Not Applicable.
PM3	N/A	Skipped per user instruction.
PM4	N/A	Skipped per user instruction. ATM VCEP also restricts PM4 to stop-loss variants only; this is a missense substitution.

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