ATM c.1641C>T, p.Thr547=
NM_000051.4:c.1641C>T
Likely Benign
This synonymous ATM variant is absent from population databases (PM2_supporting), has multiple computational predictions supporting no impact on splicing or protein function (BP4, BP7), and is reported as benign by a reputable source (BP6). The accumulation of four supporting benign criteria leads to a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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.1641C>T
Protein Change
T547=
Location
Exon 11
(Exon 11 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.1641C>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
Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as 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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.14
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 Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows it is a synonymous change (T547=) with no predicted loss-of-function and no impact on splicing. Therefore, this criterion is not applied because PVS1 applies only to null variants in a gene where loss-of-function is a known mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.' The evidence for this variant shows no amino acid change (synonymous). Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is de novo occurrence in a patient with the disease and no family history. There is no data on de novo status for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (functional studies) requires a variant to fail to rescue ATM-specific features. No functional assay data are available for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is case-control data with significant association (p ≤ 0.05, OR ≥ 2). No case-control data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is location in a mutational hot spot or well‐studied functional domain. This synonymous variant does not lie in a known functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Frequency ≤.001% if n=1 in a single sub population ... use PM2_supporting.' The evidence for this variant shows absence from gnomAD (MAF = 0%). Therefore, PM2 is applied at Supporting strength because the variant is extremely rare/absent in control populations.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive trans observations.' There is no evidence of this variant being observed in trans with a pathogenic variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Use for stop-loss variants.' This variant is synonymous and does not affect protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Supporting Use for genomic frameshift and truncating variants ...'. This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is assumed de novo without confirmation. There is no de novo evidence. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is segregation in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is a missense variant in a gene with low rate of benign missense variation. This variant is synonymous. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Protein: REVEL >.7333; RNA: predictor shows splicing impact.' The evidence shows SpliceAI predicts negligible impact (max score 0.02) and CADD score -0.14. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is patient’s phenotype highly specific for a disease with a single genetic etiology. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is a reputable source reports pathogenic. ClinVar reports this variant as benign. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Filtering Allele Frequency >.5%.' The variant is absent in population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Filtering Allele Frequency >.05%.' The variant is absent in population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is observation in healthy adult individuals for a recessive disorder. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Moderate/Supporting if functional assays show rescue of ATM-specific features.' No functional rescue data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is lack of segregation in affected family members. No family data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is a missense variant in a gene where only truncating variants cause disease. This variant is synonymous. Therefore, BP1 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.' No evidence supports this. Therefore, BP2 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 regions. Not applicable to this synonymous SNV. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence support no impact on gene or gene product.' The evidence shows SpliceAI predicts no splicing impact and CADD score of -0.14 indicates no deleterious effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is when a variant is found in a gene for which another variant causes the phenotype. Not applicable. Therefore, BP5 is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Can be considered for BP7_(RNA); Use for synonymous variants defined as ...' The variant is synonymous and SpliceAI predicts no impact on splicing. Therefore, BP7 is applied at Supporting strength.