ATM c.2839-18dup, p.?
NM_000051.4:c.2839-18dup
Likely Benign
The ATM intronic duplication c.2839-18dup receives two Supporting benign criteria (BP4, BP6) per VCEP and ACMG guidelines, with no evidence of splice impact, no functional or segregation support for pathogenicity, and benign classification reported in ClinVar. Thus, it is classified as Likely Benign.
ACMG/AMP Criteria Applied
BP4
BP6
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.2839-18dup
Protein Change
?
Location
Exon 18
(Exon 18 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.2839-18dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00759%
Rare
Highest in Population
East Asian
0.104%
Common
Global: 0.00759%
East Asian: 0.104%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250346Alt: 19Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00759%, 19/250346 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.104%, 19/18282 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 LB
2 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratories).
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
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree". The evidence for this variant shows it is an intronic duplication at position -18, outside the canonical splice acceptor/donor sites and with no predicted effect on splicing. Therefore, this criterion is not applied because the variant does not meet any of the loss-of-function categories in the ATM PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 applies to protein changes with identical amino acid alteration. The evidence for this variant shows no change to the encoded amino acid (intronic duplication). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Moderate Strength: Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity; Supporting Strength: Use when it fails to rescue an ATM specific feature only." The evidence for this variant shows no functional studies assessing ATM activity. Therefore, this criterion is not applied due to lack of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control data)." The evidence for this variant shows no case-control studies. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-studied functional domain without benign variation." The evidence for this variant shows it is an intronic duplication, not in a known functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Frequency ≤ 0.001% if n=1 in a single subpopulation; n>1 in one or multiple subpopulations would not be considered rare." The evidence for this variant shows a MAF of 0.00759% with 19 alleles observed. Therefore, this criterion is not applied because the frequency exceeds the VCEP threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows no data on trans occurrence in recessive cases. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat regions." The evidence for this variant shows an intronic duplication not predicted to alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; apply to splice variants only when PVS1_VS(RNA) applies." The evidence for this variant shows neither a truncating event nor demonstrated splice impact. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." 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, the rule for PP1 is: "Co-segregation with disease 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, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism." This is an intronic duplication, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein REVEL >0.7333 or RNA: predictor shows impact on splicing." The evidence for this variant shows SpliceAI predicts no significant splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but evidence not available." The evidence for this variant shows ClinVar reports benign/likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand-alone: Filtering allele frequency >0.5%." The evidence for this variant shows a MAF of 0.00759%, well below the threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Filtering allele frequency >0.05%." The evidence for this variant shows a MAF of 0.00759%, below the threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder." The evidence for this variant shows no data on observation in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Moderate: Functional studies show rescue of ATM features AND radiosensitivity; Supporting: rescue of either feature." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." 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, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease." This is an intronic duplication, not a missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table for observations in trans with a pathogenic variant." 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, the rule for BP3 is: "In-frame deletions/insertions in repetitive region without a known function." The evidence for this variant shows an intronic duplication not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Protein Analysis: Metapredictor REVEL score ≤ .249; RNA: no predicted impact on splicing (e.g., SpliceAI)." The evidence for this variant shows SpliceAI predicts no significant effect on splicing (max delta score 0.16). Therefore, this criterion is applied at Supporting strength because computational evidence indicates no deleterious impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows no such alternate cause reported. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence not available." The evidence for this variant shows ClinVar entries: Benign (2 labs) and Likely benign (1 lab). Therefore, this criterion is applied at Supporting strength because a reputable source classifies it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7_(RNA) is: "Supporting for synonymous and deep intronic variants defined as >+7 or <-40 from splice sites." The evidence for this variant shows it is at -18 from the acceptor site, which is within the splice region. Therefore, this criterion is not applied.