ATM c.7785T>C, p.Asp2595=
NM_000051.4:c.7785T>C
Likely Benign
The c.7785T>C (D2595=) synonymous change in ATM is extremely rare, lacks evidence for splicing or functional impact, and is reported as benign by multiple reputable sources. Based on PM2_Supporting, BP4, and BP6, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
PM2
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.7785T>C
Protein Change
D2595=
Location
Exon 52
(Exon 52 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.7785T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000399%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000883%
Very Rare
Global: 0.000399%
European (non-Finnish): 0.000883%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250852Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000399%, 1/250852 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000883%, 1/113278 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Likely Benign
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
5 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Clinical Statement
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as likely benign (1 clinical laboratories) and 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: 0.44
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: PVS1 applies to null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) per ATM PVS1 decision tree. The evidence shows this is a synonymous variant (D2595=) not predicted to affect splicing. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: PS1 applies when a different nucleotide change results in the same amino acid change as a known pathogenic variant with splicing ruled out. This is a synonymous change with no amino acid alteration. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS2 applies for confirmed de novo variants with parental testing. No de novo or parental data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: PS3 requires functional studies showing failure to rescue ATM-specific features and radiosensitivity. No functional data are available. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: PS4 requires case-control or statistical evidence (p≤.05 and OR≥2). No case-control data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM1 applies to variants in well-established functional domains or mutational hotspots. This synonymous variant is not in a known hotspot or critical domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: PM2_Supporting applies when frequency ≤0.001% with n=1 in a single subpopulation. The variant has MAF=0.000883% (1/113278) in European (non-Finnish) gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies for recessive disorders with observed trans alleles. No compound heterozygous or trans data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM4 applies to protein length changes due to in-frame indels or stop-loss. This is a synonymous variant. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5 applies to novel missense changes at the same codon as a known pathogenic variant. This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM6 applies to assumed de novo without parental confirmation. No such data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP1 applies with co-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: PP2 applies to missense variants in genes with low benign variation where missense is a common mechanism. This variant is synonymous. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: PP3_Supporting applies when REVEL>0.7333 or RNA predictors show impact on splicing. SpliceAI score=0.01 indicates no splicing impact and REVEL not elevated. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP4 applies when the patient’s phenotype is highly specific for a single gene disorder. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP5 applies when a reputable source reports variant as pathogenic without evidence. This variant is reported as benign. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: BA1 applies for allele frequency >0.5%. This variant’s frequency is 0.000399%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: BS1 applies for allele frequency >0.05%. Frequency is below this threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS2 applies when observed in healthy adult individuals for a dominant disorder. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 requires functional studies showing rescue of ATM-specific features and radiosensitivity. No functional evidence of rescue is available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS4 applies for non-segregation in affected members. No segregation data are available. 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 truncating variants cause disease. This is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: BP2 applies for observed cis/trans occurrences reducing likelihood of pathogenicity. No allelic phase data are available. 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. This is synonymous. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines: BP4 applies when multiple lines of computational evidence suggest no impact on gene or gene product. In silico predictors (CADD=0.44) and SpliceAI=0.01 predict no effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP5 applies when variant found in a case with an alternate molecular basis for disease. No such data are available. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines: BP6 applies when a reputable source reports variant as benign without available evidence. ClinVar reports this variant as Likely benign/Benign. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: BP7_Supporting applies to synonymous variants with no predicted splicing impact located outside canonical splice regions. Although SpliceAI=0.01, BP7 is not applied to avoid overlap with BP4. Therefore, BP7 is not applied.