ATM c.2376+1G>T, p.Splice_Site
NM_000051.4:c.2376+1G>T
Pathogenic
NM_000051.4:c.2376+1G>T is classified as Likely Pathogenic based on PVS1_VeryStrong for canonical splice site loss, supported by absence from controls (PM2), strong splicing predictions (PP3), and reputable ClinVar reports (PP5).
ACMG/AMP Criteria Applied
PVS1
PM2
PP3
PP5
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.2376+1G>T
Protein Change
Splice
Location
Exon 15
(Exon 15 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.2376+1G>T
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
2 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The c.2376+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 14 of the ATM gene. Another variant affecting the same nucleotide, c.2376+1G>A, has been reported in a compound heterozygous state in an individual diagnosed with ataxia-telangiectasia (Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as a disease-causing mutation.
This sequence change affects a donor splice site in intron 15 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 22213089, 26681312). ClinVar contains an entry for this variant (Variation ID: 181927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 6.34
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the PVS1 rule is: "Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows NM_000051.4:c.2376+1G>T disrupts the canonical +1 splice donor site in ATM, a known LOF mechanism. Therefore, this criterion is applied at Very Strong strength because a +1 splice site variant is considered a null variant in a gene where LOF is disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies to protein changes with an established amino acid alteration. The evidence for this variant shows a splice site change rather than an amino acid substitution. Therefore, PS1 is not applied because the variant does not result in a protein-level change matching a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. The evidence for this variant shows no information on de novo status. Therefore, PS2 is not applied due to lack of parental testing data.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires ATM-specific functional studies showing failure to rescue ATM features or radiosensitivity. The evidence for this variant shows no functional characterization. Therefore, PS3 is not applied because requisite functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires statistically significant case-control or proband data. The evidence for this variant shows no such data. Therefore, PS4 is not applied due to absence of case-control or proband counts.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants located in mutational hotspots or critical domains. The evidence for this variant shows a splice site change not in a known domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the PM2 rule is: "Supporting Frequency ≤.001% if n=1 in a single sub population...". The evidence for this variant shows absence from gnomAD (0% frequency). Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive trans configurations per ATM PM3/BP2 table. The evidence for this variant shows no information on phase with another pathogenic allele. Therefore, PM3 is not applied due to missing trans-phase data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels, stop-loss). The evidence for this variant shows a splice donor site alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5_supporting applies to certain splice variants with observed RNA impact upstream of Arg3047 and PVS1_VS(RNA). The evidence for this variant shows no observed RNA data. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo without confirmation. The evidence for this variant shows no de novo assumption. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires segregation data. The evidence for this variant shows no family segregation information. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when a gene has low benign missense variation. The evidence for this variant shows a splice site change; PP2 is not relevant. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 is: "Supporting RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence for this variant shows SpliceAI scores of 0.97/0.95 predicting splice disruption. Therefore, PP3 is applied at Supporting strength because computational tools predict a deleterious splicing effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a phenotype highly specific to ATM deficiency. The evidence for this variant shows no phenotype data. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Reputable source recently reports variant as pathogenic but evidence not available". The evidence for this variant shows ClinVar entries as Likely pathogenic/pathogenic. Therefore, PP5 is applied at Supporting strength because a reputable database reports it as pathogenic without underlying evidence.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires allele frequency >0.5%. The evidence for this variant shows 0% frequency. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires allele frequency >0.05%. The evidence for this variant shows 0% frequency. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 requires observation in healthy adults. The evidence for this variant shows no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires ATM-specific functional rescue data. The evidence for this variant shows no functional data. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of segregation in affected family members. The evidence for this variant shows no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only LOF is pathogenic. The evidence for this variant shows a splice site, not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies per PM3/BP2 table for cis observations. The evidence for this variant shows no cis data. Therefore, BP2 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 a splice site change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies when in silico tools indicate a benign effect. The evidence for this variant shows damaging splicing predictions. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 requires an alternate molecular cause in a case. The evidence for this variant shows no such case data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a benign classification. The evidence for this variant shows no benign reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or deep intronic variants without splice impact. The evidence for this variant shows a canonical splice site disruption. Therefore, BP7 is not applied.