Classification rationale

BP4BP7 Likely Benign

ATM c.5868C>T synonymous · exon 39

Likely Benign: BP4 supporting - SpliceAI maximum delta score 0.053 is at or below the ATM VCEP's <=0.1 no-predicted-splice-impact cutoff for a synonymous variant. Likely Benign: BP7 supporting - synonymous p.(Leu1956=) sits 55-110 nt from the nearest splice site, outside the +7/-21 window, with no predicted splice impact.

BP4 + BP7 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting: SpliceAI maximum delta 0.053 is at or below the ATM VCEP BP4 no-impact threshold of <=0.1.

Variant consequence settled before scoring: NM_000051.4:c.5868C>T is synonymous (NP_000042.3:p.(Leu1956=)), a non-missense change for which splicing is the primary plausible mechanism, so BP4 was evaluated only through the SpliceAI path and no missense predictor was used; prefetch confirms REVEL found=false.ClinGen HBOP ATM VCEP v1.6 BP4 supporting rule: 'Missense: REVEL score <=.249; Splicing: No predicted impact via splicing (SpliceAI <=0.1).' The VCEP instructions state SpliceAI is its sole splice predictor and that PP3 applies at SpliceAI >=0.2 while BP4 applies at SpliceAI <=0.1 (Walker et al. 2023; Jaganathan et al. 2019, Cell, PMID:30661751).Lab curator note in the ATM VCEP materials (BP4 missense/splicing policy): for BP4 evaluate exactly one applicable mechanism per variant; missense variants use only the REVEL sub-path, while non-missense variants for which splicing is the primary plausible mechanism (synonymous, intronic outside the canonical +/-1,2 donor/acceptor positions) use the splicing sub-path as the VCEP specifies. This variant is synonymous, so the splicing sub-path is the correct choice and the override does not change the outcome.

cspec ↗spliceai ↗

BP7 supporting Benign

Met at supporting: synonymous p.Leu1956= variant, 55-110 nt from the nearest splice site, with SpliceAI maximum delta 0.053 showing no splice impact.

NM_000051.4:c.5868C>T normalises to NP_000042.3:p.(Leu1956=) (p.L1956=) - a synonymous, non-protein-changing change - which brings it inside BP7's scope.ClinGen HBOP ATM VCEP v1.6 BP7 supporting rule: 'Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively', with the VCEP's own instructions adding that BP7 'is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect' and that BP4 may be applied alongside it.Exon 39 in the governing ATM table (Suppl_TableS1_PMID 40580951.xlsx) spans hg38 chr11:108310155-108310320 (166 positions, 498 SNV rows, three per position, confirming the table is complete across the exon); the variant at hg38 chr11:108310265 is therefore exon position 111, i.e. 110 nt from the acceptor boundary and 55 nt from the donor boundary, well outside the +7/-21 splice region.

cspec ↗spliceai ↗

Assessed · not applied · 13 not met · 1 not assessed

Pathogenic

PS1 Not met: c.5868C>T is synonymous with SpliceAI max delta 0.053, below the 0.2 threshold needed to enter the PS1 splicing table, and no pathogenic variant exists at residue 1956.

PS3 Not met: the only Table S1 entry for c.5868C>T is DeepATM_predicted=Yes, a computational extrapolation, so no functional assay supports PS3.

PS4 Not met: no case-control study exists for c.5868C>T, so the VCEP-required p ≤ 0.05 with odds ratio or relative risk ≥ 2 cannot be shown.

PM2 Not met: highest gnomAD subpopulation frequency 0.0294% (South Asian) is ~29-fold above the ATM VCEP's <=0.001% PM2 threshold.

PM3 Not met: zero PM3 points from unrelated A-T probands (VCEP threshold 1 point), and gnomAD grpmax filtering AF 0.0118% exceeds the VCEP's 0.01% PM3 frequency ceiling.

PM5 Not met: PM5 applies only to NMD-prone truncating variants receiving PVS1 at Very Strong, and c.5868C>T is a synonymous change with no premature stop codon.

PP1 Not assessed: no affected-relative genotypes or pedigree data exist, so PP1's autosomal-recessive threshold of >=1 affected relative cannot be tested.

PP3 Not met: SpliceAI maximum delta 0.053 is below the ATM VCEP PP3 supporting threshold of >=0.2.

PP5 Not met: ClinVar VCV000453600 has zero expert-panel submissions, all seven entries being single-submitter laboratory assertions, so PP5 cannot trigger.

Benign

BA1 Not met: highest gnomAD Grpmax Filtering AF 0.0153% versus the ATM VCEP's >0.5% BA1 threshold.

BS1 Not met: highest gnomAD Grpmax Filtering AF 0.0153% versus the ATM VCEP's >0.05% BS1 threshold.

BS3 Not met: the sole Table S1 entry for c.5868C>T is a computational prediction (DeepATM_predicted=Yes), not a measured rescue of ATM function.

BP2 Not met: zero BP2 points — no unaffected adult carrier in trans with a pathogenic ATM variant, and gnomAD reports 0 homozygotes (threshold -1 point).

BP6 Not met: no expert-panel ClinVar classification exists for c.5868C>T; the aggregate two-star Benign/Likely benign label from seven laboratories does not qualify.

N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · BS2 · BS4 · BP1 · BP3 · BP5

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.30164e-05; MAF= 0.00130%, 21/1613354 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000186694; MAF= 0.01867%, 17/91058 alleles, homozygotes = 0); grpmax FAF= 0.00011841.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.58446e-05; MAF= 0.00358%, 9/251084 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00029406; MAF= 0.02941%, 9/30606 alleles, homozygotes = 0); grpmax FAF= 0.0001526.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0013% · 21 / 1,613,354
0 hom · FAF 0.012%

South Asian 17 / 91,058	0.019%
Remaining individuals 4 / 62,478	0.0064%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0036% · 9 / 251,084
0 hom · FAF 0.015%

South Asian

9 / 30,606

0.029%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 453600)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

PMID 40580951

PMID 40580951 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP4 supporting

Searched for a pre-assigned BP4 code; none is assigned, and the row's DeepATM model call (Computational prediction, not a direct assay) is weak non-independent corroboration of the benign direction only.

→BP7 supporting

Confirms the variant is a synonymous L1956L change in exon 39, which is what brings it into BP7 scope, and supplies the hg38 exon 39 coordinates used for the splice-region position check; assigns no BP7 code.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR

24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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