ATM c.6475T>G, p.Cys2159Gly
NM_000051.4:c.6475T>G
COSMIC ID: COSM9993721
Variant of Uncertain Significance (VUS)
No ACMG/VCEP criteria are met; in the absence of supporting or benign evidence, the variant remains classified as a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
No ACMG/AMP criteria definitively applied.
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.6475T>G
Protein Change
C2159G
Location
Exon 45
(Exon 45 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2159 in gene ATM
Alternate Identifiers
COSM9993721
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.6475T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00283%
Rare
Highest in Population
African/African American
0.032%
Low Frequency
Global: 0.00283%
African/African American: 0.032%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282836Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00283%, 8/282836 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.032%, 8/24968 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
8 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (8 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
No evidence of other pathogenic variants at position 2159 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.393
0.393
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 4.45polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: “Use ATM PVS1 Decision Tree” which applies to null variants causing loss of function. The evidence for this variant shows it is a missense change (Cys2159Gly), not a predicted null allele. Therefore, this criterion is not applied because PVS1 is reserved for LOF variants and this is a missense.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: “Use for protein changes as long as splicing is ruled‐out for both alterations.” The evidence shows no previously established pathogenic variant resulting in Cys2159Gly. Therefore, PS1 is not applied because there is no existing pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS2 requires confirmed de novo occurrence. The evidence for this variant shows no information on parental testing or de novo status. Therefore, PS2 is not applied due to lack of de novo confirmation data.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: PS3 requires functional studies showing failure to rescue ATM‐specific features. The evidence shows no functional characterization for Cys2159Gly. Therefore, PS3 is not applied because no functional data are available.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PS4 requires statistically significant case‐control data or proband counting. There are no published case‐control studies or sufficient proband data for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM1 applies to variants in mutational hot spots or critical functional domains. There is no evidence that Cys2159 lies within a defined hotspot or critical domain. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines: “Frequency ≤0.001% if n=1 in a single subpopulation” qualifies for PM2_supporting. The evidence shows MAF=0.00283% with n=8 alleles. Therefore, PM2 is not applied because the allele count and frequency exceed the VCEP‐specified threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies to recessive disorders when in trans with a pathogenic variant. There is no evidence of trans phase with a known pathogenic ATM variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM4 applies to protein length changes (in‐frame indels or stop‐loss). This is a missense change without length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: PM5_supporting applies when a novel missense occurs at a residue with a different known pathogenic missense. No other pathogenic variant at residue 2159 is reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: PM6 applies to presumed de novo variants without parental confirmation. No de novo assumption has been made. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP1 requires cosegregation with disease 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 missense variation. ATM tolerates missense variation and has many benign/transitional variants. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: “PP3 supporting if REVEL >0.7333 or splicing predictor shows impact.” The evidence shows REVEL=0.39 and SpliceAI Δscore=0.13, indicating no predicted impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP4 requires a highly specific phenotype or family history. 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 classifies the variant as pathogenic. ClinVar reports VUS or Likely benign. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: BA1 stand‐alone if allele frequency >0.5%. The observed frequency is 0.00283%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: BS1 strong if allele frequency >5%. The observed frequency is 0.00283%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS2 applies when variant observed in healthy adults inconsistent with disease penetrance. No such observations are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 requires functional evidence of rescue of ATM activity. No functional rescue data exist. 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. No such data are provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP1 applies to missense in genes where only truncating variants cause disease. ATM has known pathogenic missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: BP2 refers to observed in cis/trans with pathogenic variant inconsistent with disease mechanism. No such data exist. 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 not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: BP4 supporting requires REVEL ≤0.249 or benign splicing prediction. REVEL=0.39 exceeds threshold; splicing Δscore=0.13 is low but RNA thresholds are not defined for benign. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP5 applies when variant found in trans with a pathogenic variant for a fully penetrant disorder. No such trans configuration is known. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP6 applies when a reputable source classifies as benign without primary data. ClinVar reports conflicting VUS/Likely benign but not unanimously benign. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP7 applies to synonymous or deep intronic variants. This is a missense change. Therefore, BP7 is not applied.