Variant classification summary

NM_000051.4:c.7875T>G

ATM · NP_000042.3:p.(Asp2625Glu) · NM_000051.4

GRCh37: chr11:108203575 T>G · GRCh38: chr11:108332848 T>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.(Asp2625Glu)

gnomAD AF

6.818483296575509e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7875T>G (p.Asp2625Glu) is a missense variant in exon 53 of ATM, observed at extremely low frequency in gnomAD v4.1 (AF = 6.82 × 10⁻⁶, 11/1,613,262 alleles), meeting PM2_Supporting.

2

In silico predictions are inconclusive: REVEL score (0.373) falls between the VCEP PP3 threshold (>0.7333) and BP4 threshold (≤0.249), and SpliceAI predicts no splicing impact (max delta = 0.07).

3

The variant is classified as 'Functional' (High confidence) in the ATM SNV combined-score table (PMID 40580951), reflecting in silico composite prediction rather than experimental functional data; no variant-specific functional assays are available.

4

ClinVar reports this variant as Pathogenic (1 submitter, criteria provided, single submitter); however, the VCEP does not use PP5/BP6, and no independent case-level or functional evidence corroborates this classification.

5

With only PM2_Supporting met and no other criteria satisfied, this variant does not reach a Likely Pathogenic or Likely Benign classification under the ACMG/AMP combination rules and is classified as a Variant of 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	PVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, exon deletion). NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu) and does not fall within the ATM PVS1 decision tree.	pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not met	PS1 requires a different nucleotide change resulting in the same amino acid substitution (p.Asp2625Glu) with a prior pathogenic or likely pathogenic classification. While c.7875T>A also encodes p.Asp2625Glu, it lacks a ClinVar classification and is not established as pathogenic or likely pathogenic. No qualifying comparator variant exists.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use for AD or AR disease — informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific experimental functional assay data are available. ATM VCEP PS3 requires rescue assay evidence (failure to rescue ATM-specific phosphorylation targets and/or radiosensitivity). The Suppl_TableS1 classification of 'Functional' reflects in silico composite prediction, not experimental functional data. No publications with variant-specific functional assays were identified.	cspec vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	No case-control studies demonstrating significantly increased prevalence of NM_000051.4:c.7875T>G in affected individuals compared to controls are available. The ClinVar submission is from a single clinical laboratory without published case-level data.	clinvar cspec
PS5	N/A	PS5 is not included in the ClinGen HBOP ATM VCEP v1.5.0 criteria set. The VCEP review committee recommends against using PP5/BP6, and PS5 falls into the same category of relying on unverified external classifications.	cspec
PM1	N/A	CSPEC 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	NM_000051.4:c.7875T>G is present in gnomAD v4.1 at an allele frequency of 6.82 × 10⁻⁶ (0.00068%; 11/1,613,262 alleles), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%. The variant is absent from gnomAD-Canada and observed at 3.99 × 10⁻⁶ in gnomAD v2.1 (1/250,866 alleles).	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM5	N/A	ATM VCEP PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants meeting specific criteria. The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu).	cspec pm5_candidates
PM6	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use for AD or AR disease — informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No co-segregation data are available for NM_000051.4:c.7875T>G. ATM VCEP PP1 applies only to autosomal recessive (A-T) conditions and requires affected relatives to carry both variants identified in the proband. No segregation studies have been published for this variant.	cspec
PP2	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use — ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	REVEL score is 0.373, below the ATM VCEP PP3 threshold of >0.7333. SpliceAI max delta is 0.07, below the splicing threshold of ≥0.2. Multiple computational predictors (REVEL, BayesDel −0.137, AlphaMissense 0.164, EVE 0.312) do not reach the consensus threshold for a deleterious prediction under the VCEP rules.	revel bayesdel spliceai cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use — breast cancer has multiple genetic etiologies, and for A-T, phenotype evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	CSPEC HBOP ATM VCEP v1.5.0: Not Applicable for this VCEP — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering AF is 5 × 10⁻⁶ (0.0005%), well below the ATM VCEP BA1 threshold of >0.5%.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering AF is 5 × 10⁻⁶ (0.0005%), well below the ATM VCEP BS1 threshold of >0.05%.	gnomad_v4 cspec
BS2	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use — ATM has incomplete penetrance.	cspec
BS3	Not met	No variant-specific experimental functional studies demonstrating normal protein function or rescue of ATM-specific features are available. The ATM kinase activity and radiosensitivity reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) do not include this variant.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use — co-segregation analysis in low-penetrance genes can lead to false positives; informative instances of lack of co-segregation in A-T families are too rare.	cspec
BP1	N/A	CSPEC HBOP ATM VCEP v1.5.0: Do not use — missense pathogenic variants are known for ATM.	cspec
BP2	Not met	No evidence of NM_000051.4:c.7875T>G occurring in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged ≥18 years. No points can be assigned under the ATM PM3/BP2 table.	cspec vcep_atm_pm3_bp2_1_5
BP4	Not met	REVEL score is 0.373, above the ATM VCEP BP4 threshold of ≤0.249 for missense variants. Although SpliceAI predicts no splicing impact (max delta 0.07 ≤ 0.1), the REVEL score does not support a benign computational prediction.	revel spliceai cspec
BP5	N/A	CSPEC 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.	cspec
BP6	N/A	CSPEC HBOP ATM VCEP v1.5.0: Not Applicable for this VCEP — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is applicable only to synonymous and deep intronic variants (intronic variants beyond +7 at donor and −21 at acceptor). NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu) and does not qualify.	cspec

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