0%
ATMc.8056T>CUncertain significance
Print report
Variant interpretation report

ATM c.8056T>C, p.(Phe2686Leu)

NM_000051.3:c.8056T>C NP_000042.3:p.(Phe2686Leu) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATM

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.5.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles; highest subpopulation NFE AF=8.48e-07, 1/1,179,832 alleles). This is well below the VCEP ATM PM2_supporting threshold of ≤0.001% (n=1 in a single subpopulation).

PP3Supporting
PP3 · supporting

REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta=0.00), consistent with a purely missense effect. BayesDel score is 0.331.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

2 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: reviewed by expert panel.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53747617, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 9 not met · 0 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2_supporting is met: the variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles), well below the VCEP ATM PM2_supporting threshold of ≤0.001%.

PP3 is met: REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. AlphaMissense is 0.98 and SpliceAI predicts no splicing impact (max delta=0.00).

No other pathogenic or benign criteria are met. PVS1, PS1, PS3, PS4, PM5, and PP1 are not applicable or not met. BA1, BS1, BS3, BP2, and BP4 are not met. Remaining criteria (PS2, PM1, PM6, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, BP7) are not applicable per VCEP ATM v1.5.0 specifications.

With PM2_supporting and PP3 as the only criteria met (two pathogenic supporting), there is insufficient evidence to classify this variant beyond Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. No benign criteria are met to trigger conflicting-evidence rules.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles; highest subpopulation NFE AF=8.48e-07, 1/1,179,832 alleles). This is well below the VCEP ATM PM2_supporting threshold of ≤0.001% (n=1 in a single subpopulation). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 1/1
  • 613
  • 950 alleles (AF=0.000062%)
  • gnomAD-Canada: absent. Single allele observed in NFE subpopulation only.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta=0.00), consistent with a purely missense effect. BayesDel score is 0.331. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.913 (>0.7333 threshold)
  • SpliceAI: max delta 0.00 (no splicing impact)
  • BayesDel: 0.331
  • AlphaMissense: 0.98 (from VCEP Suppl_TableS1).
Sources
revelspliceai ↗bayesdel

Not met · 9 · evaluated, threshold not reached

PS1 No known pathogenic or likely pathogenic missense variant at the same residue (p.Phe2686) with a different amino acid change was identified in ClinVar or VCEP reference datasets. PS1 requires a comparator variant at the same residue with established pathogenicity. Details ▾Hide ▴
Evidence considered
  • No expert-panel P/LP variant at residue 2686 identified in ClinVar or VCEP supplementary tables.
Sources
clinvar ↗
PS3 No variant-specific experimental functional assay data (kinase activity or radiosensitivity rescue) are available for p.Phe2686Leu. The VCEP-approved Suppl_TableS1 (PMID 40580951) provides computational combined functional scores only; the 'Non-functional' classification derives from in silico predictions (boostDM, EVE, REVEL, AlphaMissense), not from experimental functional assays. VCEP PS3 requires laboratory-based functional evidence demonstrating failure to rescue ATM kinase activity and/or radiosensitivity. Details ▾Hide ▴
Evidence considered
  • Suppl_TableS1 combined score for c.8056T>C: classification=Non-functional
  • but this is computational prediction
  • not experimental functional assay data.
Still missing
  • No experimental functional studies (kinase assay
  • radiosensitivity assay) performed on this variant.
Sources
vcep_suppl_tables1_pmid_40580951
PS4 No case-control study demonstrating statistically significant enrichment of this variant in affected individuals. VCEP ATM PS4 requires a case-control study with p-value ≤0.05 AND (OR/RR/HR ≥2 OR lower 95% CI ≥1.5). One proband (AT1083, PMID 31429931) carried this variant in compound heterozygous state with a pathogenic splice variant, but a single case observation does not meet the case-control threshold. Details ▾Hide ▴
Evidence considered
  • Patient AT1083: compound heterozygous c.8056T>C + c.8151+1G>A
  • diagnosed with ataxia-telangiectasia. Single case
  • no case-control statistics available.
Still missing
  • No case-control or cohort enrichment data for this variant.
Sources
PMID:31429931 ↗
PP1 No segregation data available for this variant. VCEP ATM PP1 requires observation in affected relatives for the autosomal recessive condition (1 relative for Supporting, 2 for Moderate, ≥3 for Strong). Details ▾Hide ▴
Evidence considered
  • No segregation analysis reported in any reviewed publication.
Still missing
  • No family segregation studies available.
BA1 gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BA1 threshold of >0.5% (Grpmax Filtering AF). The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.000062%
  • grpmax_faf=null. Far below 0.5% threshold.
Sources
gnomad_v4 ↗
BS1 gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BS1 threshold of >0.05% (Grpmax Filtering AF). The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: AF=0.000062%
  • far below 0.05% threshold.
Sources
gnomad_v4 ↗
BS3 No experimental functional data demonstrating rescue of ATM kinase activity or radiosensitivity for p.Phe2686Leu. VCEP BS3 requires variant-specific functional rescue data (both ATM-specific feature AND radiosensitivity for moderate; either for supporting). No such data available. Details ▾Hide ▴
Evidence considered
  • No published functional rescue assays identified for this variant.
Still missing
  • No functional rescue studies (kinase assay
  • radiosensitivity rescue) for this variant.
BP2 No observation of this variant in trans with a pathogenic variant in an unaffected (non-A-T) individual. VCEP ATM BP2 requires co-occurrence data in unaffected individuals with point assignments per the PM3/BP2 table. Details ▾Hide ▴
Evidence considered
  • No unaffected individuals reported with this variant in trans with a P/LP variant.
Still missing
  • No co-occurrence data in unaffected individuals.
BP4 REVEL score of 0.913 far exceeds the VCEP ATM BP4 threshold of ≤0.249 for missense variants. Multiple in silico tools predict a deleterious effect (REVEL 0.913, AlphaMissense 0.98, BayesDel 0.331). Computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.913 (threshold ≤0.249 for BP4)
  • AlphaMissense: 0.98
  • BayesDel: 0.331. All above benign thresholds.
Sources
revelbayesdel
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Phe2686Leu); PVS1 under VCEP ATM v1.5.0 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion). Details ▾Hide ▴

No further detail was recorded.

PS2 VCEPVCEP HBOP ATM v1.5.0 deems PS2 not applicable. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPVCEP HBOP ATM v1.5.0 deems PM1 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
PM3 N/ASkipped per case instructions; PM3 was excluded from assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AMissense variant; VCEP ATM PM4 applies only to stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AMissense variant. VCEP ATM PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with observed splicing impact where PVS1_VS(RNA) is applied. Details ▾Hide ▴
Sources
cspec ↗
PM6 VCEPVCEP HBOP ATM v1.5.0 deems PM6 not applicable. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPVCEP HBOP ATM v1.5.0 deems PP2 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
PP4 VCEPVCEP HBOP ATM v1.5.0 deems PP4 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPVCEP HBOP ATM v1.5.0 deems PP5 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BS2 VCEPVCEP HBOP ATM v1.5.0 deems BS2 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BS4 VCEPVCEP HBOP ATM v1.5.0 deems BS4 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPVCEP HBOP ATM v1.5.0 deems BP1 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPVCEP HBOP ATM v1.5.0 deems BP3 not applicable. Details ▾Hide ▴

No further detail was recorded.

BP5 VCEPVCEP HBOP ATM v1.5.0 deems BP5 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPVCEP HBOP ATM v1.5.0 deems BP6 not applicable for ATM. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/AMissense variant (p.Phe2686Leu). VCEP ATM BP7 applies only to synonymous and deep intronic variants (further than +7 at donor or -21 at acceptor sites), or to silent/intronic variants with observed lack of aberrant RNA splicing. This is a coding missense change. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/APS5 is not specified in the VCEP HBOP ATM v1.5.0 framework. Under generic ACMG/AMP, no authoritative source has recently and definitively classified this variant as pathogenic with evidence unavailable for independent review. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.3
Coding (HGVS c.)
NM_000051.3:c.8056T>C
Protein (HGVS p.)
NP_000042.3:p.(Phe2686Leu)
GRCh38
chr11:108335014 T>C
GRCh37
chr11:108205741 T>C
ClinVar
490724
COSMIC
COSV53747617

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.3. Select a row to find it on the plot.

ATMNM_000051.3
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,950 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,950 alleles · 0 hom
European (non-Finnish)1 / 1,179,832 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19598e-07; MAF= 0.00006%, 1/1613950 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47578e-07; MAF= 0.00008%, 1/1179832 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +61 bp
0.000
SpliceAI acceptor gainat +25 bp
0.000
SpliceAI donor lossat -16 bp
0.000
SpliceAI donor gainat +27 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.913
BayesDel
0.331

How the predictions were used

PP3 SupportingREVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta=0.00), consistent with a purely missense effect. BayesDel score is 0.331. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.913 (>0.7333 threshold)
  • SpliceAI: max delta 0.00 (no splicing impact)
  • BayesDel: 0.331
  • AlphaMissense: 0.98 (from VCEP Suppl_TableS1).
Sources
revelspliceai ↗bayesdel
BP4 REVEL score of 0.913 far exceeds the VCEP ATM BP4 threshold of ≤0.249 for missense variants. Multiple in silico tools predict a deleterious effect (REVEL 0.913, AlphaMissense 0.98, BayesDel 0.331). Computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.913 (threshold ≤0.249 for BP4)
  • AlphaMissense: 0.98
  • BayesDel: 0.331. All above benign thresholds.
Sources
revelbayesdel
BP7 N/AMissense variant (p.Phe2686Leu). VCEP ATM BP7 applies only to synonymous and deep intronic variants (further than +7 at donor or -21 at acceptor sites), or to silent/intronic variants with observed lack of aberrant RNA splicing. This is a coding missense change. Details ▾Hide ▴
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.331457.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion.
    Austen B et al. · 2007
    Investigated residual ATM allele mutation status in 72 CLL tumors with 11q deletion. NM_000051.3:c.8056T>C was not mentioned in the abstract; no full text available for confirmation.
    Does not name this variant
    PMID 17968022 ↗
  • 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.
    Richards S et al. · 2015
    ACMG/AMP standards and guidelines for interpretation of sequence variants. NM_000051.3:c.8056T>C was not mentioned in the full text.
    Does not name this variant
    PMID 25741868 ↗
  • Hereditary Ataxia Overview.
    Adam MP et al. · 1993
    GeneReviews overview of hereditary ataxia. NM_000051.3:c.8056T>C was not mentioned; the publication is a gene-level clinical summary.
    Does not name this variant
    PMID 20301317 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    GeneReviews entry on ataxia-telangiectasia. NM_000051.3:c.8056T>C was not mentioned; the publication is a gene-level clinical summary.
    Does not name this variant
    PMID 20301790 ↗
  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    van de Warrenburg BP et al. · 2014
    EFNS/ENS consensus on diagnosis and management of chronic ataxias in adulthood. NM_000051.3:c.8056T>C was not mentioned; the publication is a clinical guideline.
    Does not name this variant
    PMID 24418350 ↗
  • 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.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. NM_000051.3:c.8056T>C was not mentioned in the full text.
    Does not name this variant
    PMID 25394175 ↗
  • Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.
    Shakya S et al. · 2019
    Patient AT1083, a 17-year-old male with age of onset 12, presented with nystagmus, slow saccades, impaired pursuit eye movement, areflexia, and mild cerebellar atrophy. Was found to be compound heterozygous for NM_000051.3:c.8056T>C (p.F2686L) and c.8151+1G>A (canonical splice variant). The paper classified c.8056T>C as Likely Pathogenic and c.8151+1G>A as Pathogenic by ACMG criteria.
    Names this variant
    PMID 31429931 ↗
    Quoted passage
    chr11:108205741;NM_000051:c.8056T>C: p.F2686L; het

    Table 1 (variant listing, lines 495-519); Table 2 (clinical features, lines 894-903)

  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    Gasser T et al. · 2010
    EFNS guidelines on molecular diagnosis of ataxias and spastic paraplegias. NM_000051.3:c.8056T>C was not mentioned; the publication is a clinical guideline.
    Does not name this variant
    PMID 20050888 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,950 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Uncertain significance · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19598e-07; MAF= 0.00006%, 1/1613950 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47578e-07; MAF= 0.00008%, 1/1179832 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 490724)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.331457.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53747617, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.