Variant classification summary

NM_000051.3:c.8751C>T

ATM · NP_000042.3:p.(Gly2917=) · NM_000051.3

GRCh37: chr11:108224572 C>T · GRCh38: chr11:108353845 C>T

Gene: ATM Transcript: NM_000051.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Gly2917=)

gnomAD AF

1.8589525917517034e-06 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This synonymous variant (NM_000051.3:c.8751C>T, p.Gly2917=) is located in exon 62 of ATM, well removed from canonical splice sites (52 nt from the donor, 97 nt from the acceptor). SpliceAI predicts no splice impact (max delta = 0.01), consistent with BP4_Supporting under the ATM HBOP VCEP v1.5.0.

2

As a synonymous variant not near splice consensus boundaries and with no predicted or observed splice defect, BP7_Supporting is met under ATM VCEP v1.5.0.

3

The variant is extremely rare in population databases: absent from gnomAD v2.1 and present at AF = 0.00019% (3/1,613,812 alleles, grpmax FAF = 6.8e-07) in gnomAD v4.1, meeting PM2_Supporting under ATM VCEP v1.5.0 (threshold ≤ 0.001%).

4

This variant has been classified as Likely Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP (ClinVar Variation ID 453745, reviewed by expert panel). Clinical laboratory submissions include Likely Benign (2 labs), Benign (1 lab), and Uncertain Significance (1 lab).

5

PVS1, PS1, and PM5 are not applicable as the variant is synonymous and does not cause a null effect, amino acid change, or premature termination codon. PS3 and BS3 functional assay data (ATM kinase/rescue assays) are not available. PS4 case-control data and PP1 segregation data are absent. BA1 and BS1 population frequency thresholds are not met. PP3 computational evidence for pathogenicity is not met.

6

Under the ATM VCEP v1.5.0 combination rules (adapted from Richards et al. 2015), the met criteria include two benign supporting criteria (BP4, BP7) and one pathogenic supporting criterion (PM2). Per the VCEP classification framework, this constellation of ≥1 Benign Supporting and ≥1 Pathogenic Supporting results in Uncertain Significance - Conflicting Evidence (Rule 31). However, the ClinGen HBOP VCEP expert panel has classified this variant as Likely Benign, suggesting additional benign evidence (such as RNA splicing data from PMID 34974520) may have been considered in the expert panel curation that is not independently verifiable from the available case materials.

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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. This is a synonymous variant (c.8751C>T, p.Gly2917=) with no predicted splice impact (SpliceAI max delta score = 0.01) and no evidence of aberrant splicing. It does not meet the ATM VCEP v1.5.0 PVS1 null-variant criteria (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion) and does not trigger PVS1_Variable(RNA) as no splice defect is observed or predicted.	cspec spliceai
PS1	N/A	PS1 is not applicable. The ATM VCEP v1.5.0 PS1 rule applies to missense changes (requiring same amino acid change as a known P/LP variant) or splicing variants with similar splice predictions. This is a synonymous variant (p.Gly2917=) with no amino acid change, and SpliceAI (max delta = 0.01) predicts no splice impact. Neither branch of the VCEP PS1 rule is triggered.	cspec spliceai
PS2	N/A	PS2 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PS2 as Not Applicable.	cspec
PS3	Not assessed	PS3 is not assessed. The ATM VCEP v1.5.0 requires functional evidence demonstrating that the variant fails to rescue ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity. No validated functional assay data meeting VCEP PS3 specifications was identified for this variant. An exploratory search identified a minigene splicing assay (Lhota et al. 2021, PMID 34974520) reportedly showing normal splicing, but (a) this could not be independently verified as full text was unavailable, and (b) normal splicing evidence does not directly fulfill VCEP PS3 criteria, which require rescue-based functional assays.
PS4	Not assessed	PS4 is not assessed. The ATM VCEP v1.5.0 requires a case-control study with p ≤ 0.05 and OR/HR/RR ≥ 2 (or lower 95% CI ≥ 1.5). No published case-control study analyzing the prevalence of c.8751C>T in affected versus control populations was identified. The variant is present at very low frequency in gnomAD v4.1 (AF = 0.00019%) and absent from gnomAD v2.1, precluding population-based enrichment analysis without dedicated case-control data.	gnomad_v4 gnomad_v2
PS5	Not met	PS5 is not met. Under generic ACMG/AMP 2015 (the ATM VCEP does not include PS5), this criterion requires a reputable source to have reported the variant as pathogenic. ClinVar submissions for this variant (Variation ID 453745) are Likely Benign (expert panel and 2 clinical laboratories), Benign (1 clinical laboratory), and Uncertain Significance (1 clinical laboratory). No reputable source has reported c.8751C>T as pathogenic.	clinvar
PM1	N/A	PM1 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PM1 as Not Applicable.	cspec
PM2	Met	PM2_Supporting is met under ATM VCEP v1.5.0. The variant frequency in gnomAD v4.1 is 0.00019% (3/1,613,812 alleles; grpmax FAF = 6.8e-07), which is ≤ 0.001%, meeting the VCEP PM2_Supporting threshold. The variant is absent from gnomAD v2.1, consistent with extreme rarity.	gnomad_v4 gnomad_v2 cspec
PM5	N/A	PM5 is not applicable. The ATM VCEP v1.5.0 PM5 rule applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with observed splice defects where PVS1_VS(RNA) is applied. This variant (c.8751C>T) is a synonymous substitution that does not create a premature termination codon and has no predicted or observed splice impact (SpliceAI max delta = 0.01). The pm5_candidates.json confirms no comparator truncating/splice variants are applicable.	cspec spliceai
PM6	N/A	PM6 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PM6 as Not Applicable.	cspec
PP1	Not assessed	PP1 is not assessed. The ATM VCEP v1.5.0 applies PP1 for autosomal recessive (A-T) conditions with segregation in affected relatives (≥1 supporting, 2 moderate, ≥3 strong). No segregation data for c.8751C>T in A-T or cancer-affected families was identified in any of the available sources.
PP2	N/A	PP2 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PP2 as Not Applicable.	cspec
PP3	Not met	PP3 is not met. The ATM VCEP v1.5.0 requires REVEL > 0.733 for missense variants or SpliceAI ≥ 0.2 for splicing variants. This is a synonymous variant; REVEL is not available (no amino acid substitution to score). SpliceAI max delta score is 0.01, well below the 0.2 threshold. No computational evidence supports a damaging effect.	spliceai cspec
PP4	N/A	PP4 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PP4 as Not Applicable.	cspec
PP5	N/A	PP5 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks PP5 as Not Applicable.	cspec
BA1	Not met	BA1 is not met. The ATM VCEP v1.5.0 requires grpmax Filtering AF > 0.5% in gnomAD v4. The observed grpmax FAF for c.8751C>T is 6.8e-07 (0.000068%), which is orders of magnitude below the 0.5% threshold. This variant is extremely rare, not a common polymorphism.	gnomad_v4 cspec
BS1	Not met	BS1 is not met. The ATM VCEP v1.5.0 requires grpmax Filtering AF > 0.05% in gnomAD v4. The observed grpmax FAF for c.8751C>T is 6.8e-07 (0.000068%), well below the 0.05% threshold. The population frequency does not support a benign interpretation.	gnomad_v4 cspec
BS2	N/A	BS2 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks BS2 as Not Applicable.	cspec
BS3	Not assessed	BS3 is not assessed. The ATM VCEP v1.5.0 requires functional evidence that the variant rescues ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity (Moderate: both; Supporting: either). No validated functional rescue assay data was identified. An exploratory search identified a minigene splicing assay (Lhota et al. 2021, PMID 34974520) reportedly demonstrating normal splicing for c.8751C>T; however, (a) full text was unavailable for independent verification, and (b) normal splicing evidence is more appropriately considered under BP7(RNA) rather than BS3 under the VCEP framework.
BS4	N/A	BS4 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks BS4 as Not Applicable.	cspec
BP1	N/A	BP1 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	BP2 is not assessed. Under the ATM VCEP v1.5.0 PM3/BP2 table, BP2 applies when the variant is observed in trans with a P/LP variant in an unaffected (non-A-T) individual, with points assigned per proband. No data on co-occurrence in trans with a known pathogenic ATM variant in unaffected individuals was identified for c.8751C>T.
BP4	Met	BP4_Supporting is met under ATM VCEP v1.5.0 (splicing path). The variant has no predicted impact on splicing: SpliceAI max delta score = 0.01, which is ≤ 0.1, meeting the VCEP BP4 threshold for benign computational splicing prediction. No REVEL score is available as this is a synonymous variant (the missense path is not applicable).	spliceai cspec
BP5	N/A	BP5 is not applicable. The ATM HBOP VCEP v1.5.0 explicitly marks BP5 as Not Applicable.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	Met	BP7_Supporting is met under ATM VCEP v1.5.0. This is a synonymous variant (c.8751C>T, p.Gly2917=) located at nucleotide position c.8751 within exon 62 (c.8654 to c.8803). The variant lies 52 nucleotides upstream of the donor site and 97 nucleotides downstream of the acceptor site, well beyond the VCEP-defined boundaries of +7 (donor) and -21 (acceptor). SpliceAI predicts no splice impact (max delta = 0.01). No aberrant RNA defect has been observed or predicted for this variant.	spliceai cspec

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