ATM c.6808-11T>G, p.?
NM_000051.4:c.6808-11T>G
Variant of Uncertain Significance (VUS)
The intronic variant c.6808-11T>G in ATM is absent from controls (PM2_supporting) and shows no computational evidence of impact (BP4_supporting). No further strong or moderate evidence supports pathogenicity or benignity, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.6808-11T>G
Protein Change
?
Location
Exon 46
(Exon 46 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.6808-11T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.19
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: ATM PVS1 Decision Tree. The rule states: apply PVS1 only for null variants (nonsense, frameshift, canonical splice +1/2) in ATM where LOF is known mechanism. The evidence for this variant shows: c.6808-11T>G is an intronic change outside the canonical ±1/2 splice sites with no demonstrated LOF. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: PS1 applies to protein changes identical to established pathogenic variants when splicing is ruled out. The evidence for this variant shows: it is intronic with no predicted protein change. Therefore, this criterion is not applied because there is no protein alteration.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS2 requires confirmed de novo occurrence. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: PS3 applies when well‐validated functional assays show a damaging effect. The evidence for this variant shows: no functional characterization exists for c.6808-11T>G. Therefore, this criterion is not applied because functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS4 requires significant case-control or segregation data. The evidence for this variant shows: no case-control or patient counting data. Therefore, this criterion is not applied due to absence of prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM1 applies to variants in mutational hot spots or critical domains. The evidence for this variant shows: location and domain impact are unknown. Therefore, this criterion is not applied because no critical domain involvement is established.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: PM2 supporting strength when frequency ≤0.001% in a single subpopulation. The rule states: "Frequency ≤.001% if n=1 in a single sub population..." The evidence for this variant shows: c.6808-11T>G is absent from gnomAD (0% frequency). Therefore, this criterion is applied at Supporting strength because the variant is extremely rare/absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies when variant observed in trans with a pathogenic variant in recessive disorder. The evidence for this variant shows: no information on trans observations. Therefore, this criterion is not applied due to lack of segregation data.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: PM4 applies to in-frame indels or stop-loss variants. The evidence for this variant shows: it is intronic without predicted in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5 supporting applies to novel missense or splice variants with PTC upstream of p.Arg3047. The evidence for this variant shows: no PTC creation or known missense position. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM6 applies to presumed de novo without confirmation. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP1 applies with cosegregation in multiple affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP2 applies to missense variants in genes with low benign missense rate. The evidence for this variant shows: intronic location and no missense effect. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: PP3 supporting requires REVEL >0.7333 or at least one in silico predictor showing splicing impact. The evidence for this variant shows: CADD score 3.19, SpliceAI max 0.21 (below impact threshold). Therefore, this criterion is not applied because computational predictions do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP4 applies when phenotype is highly specific for gene. The evidence for this variant shows: no patient phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP5 applies when a reputable source classifies variant as pathogenic. The evidence for this variant shows: absent from ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BA1 applies when allele frequency >5%. The evidence for this variant shows: 0% frequency. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS1 applies when allele frequency is greater than expected for disorder. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS2 applies when variant observed in healthy adult for dominant disorders. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 applies when functional assays show rescue of ATM function. The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS4 applies with non-segregation in affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP1 applies to missense variants in genes where only truncating variants cause disease. The evidence for this variant shows: intronic location. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: BP2 applies when variant observed in trans with a pathogenic variant in recessive disorder. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: an intronic SNV. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines: BP4 applies when multiple computational lines suggest no impact. The rule states: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: CADD score 3.19 (benign range) and SpliceAI max score 0.21 (below threshold for splicing impact). Therefore, this criterion is applied at Supporting strength because computational evidence supports benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP5 applies when variant found in a case with an alternate molecular basis. The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP6 applies when a reputable source classifies variant as benign without evidence. The evidence for this variant shows: no such external classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: BP7 applies to synonymous or deep intronic variants (>±40 from splice sites). The evidence for this variant shows: location c.6808-11 is within 40 nucleotides of acceptor site. Therefore, this criterion is not applied.