ATM c.8861A>G, p.Tyr2954Cys
NM_000051.4:c.8861A>G
COSMIC ID: COSM1289465
Variant of Uncertain Significance (VUS)
The variant NM_000051.4:c.8861A>G (Y2954C) in ATM remains classified as VUS. Only PP3 supporting evidence (REVEL>0.7333) is met, which is insufficient for pathogenic or benign classification under ACMG/VCEP guidelines.
ACMG/AMP Criteria Applied
PP3
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.8861A>G
Protein Change
Y2954C
Location
Exon 62
(Exon 62 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2954 in gene ATM
Alternate Identifiers
COSM1289465
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.8861A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00106%
Rare
Highest in Population
European (Finnish)
0.00398%
Rare
Global: 0.00106%
European (Finnish): 0.00398%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282746Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00106%, 3/282746 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.00398%, 1/25118 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The p.Y2954C variant (also known as c.8861A>G), located in coding exon 61 of the ATM gene, results from an A to G substitution at nucleotide position 8861. The tyrosine at codon 2954 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 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 2954 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.897
0.897
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
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.16
Neutral: Show all
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: Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease. The evidence for this variant shows: Y2954C is a missense change, not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant requirement.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: Use for protein changes as long as splicing is ruled-out for both alterations. The evidence for this variant shows: No previously established pathogenic variant at amino acid Y2954. Therefore, this criterion is not applied because there is no matching established pathogenic protein change.
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 information on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. The evidence for this variant shows: No functional studies have been performed. Therefore, this criterion is not applied due to absence of functional assay data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: Strong case-control studies; p-value ≤.05 AND (odds ratio ≥2 OR lower 95% CI ≥1.5). The evidence for this variant shows: No case-control data available. Therefore, this criterion is not applied due to lack of statistical case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: Located in a mutational hot spot and/or critical and well-established functional domain without benign variation. The evidence for this variant shows: No information that Y2954 lies within a critical domain or hotspot. Therefore, this criterion is not applied because domain/hotspot data are lacking.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply. The evidence for this variant shows: MAF = 0.00106% with 3/282746 alleles across multiple populations. Therefore, this criterion is not applied because the allele frequency exceeds the VCEP threshold and is observed in multiple subpopulations.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: Use observation of variant in trans with a pathogenic variant for recessive disorders per ATM PM3/BP2 table. The evidence for this variant shows: No data on allelic phase or trans observations. Therefore, this criterion is not applied due to absence of allelic phase information.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: Protein length changes due to in-frame indels or stop-loss. The evidence for this variant shows: Y2954C is a missense substitution, not an indel or stop-loss. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047 or supporting for splice variants. The evidence for this variant shows: Y2954C is a missense change and no other pathogenic missense has been reported at this residue. Therefore, this criterion is not applied because conditions for PM5 are not met.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: De novo (without confirmation of paternity and maternity). The evidence for this variant shows: No de novo evidence. Therefore, this criterion is not applied due to absence of de novo data.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: Cosegregation with disease in multiple affected family members. The evidence for this variant shows: No segregation data. Therefore, this criterion is not applied because family study data are missing.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: Missense variant in gene with low rate of benign missense variants. The evidence for this variant shows: ATM has both pathogenic and benign missense reported, and no gene-specific support for applying PP2. Therefore, this criterion is not applied due to unclear missense constraint context.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing. The evidence for this variant shows: REVEL score = 0.90, multiple algorithms predict damaging effect, SpliceAI shows no splicing impact. Therefore, this criterion is applied at Supporting strength because the REVEL score exceeds the VCEP threshold indicating deleterious effect.
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 specific clinical phenotype provided. Therefore, this criterion is not applied due to lack of phenotype data.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: Reputable source reports variant as pathogenic. The evidence for this variant shows: ClinVar entries are all VUS. Therefore, this criterion is not applied because no authoritative pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: Filtering Allele Frequency >.5%. The evidence for this variant shows: MAF = 0.00106%, well below BA1 threshold. Therefore, this criterion is not applied because allele frequency does not exceed the stand-alone benign threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: Filtering Allele Frequency >.05%. The evidence for this variant shows: MAF = 0.00106%, below BS1 threshold. Therefore, this criterion is not applied because allele frequency is not high enough for strong benign evidence.
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 with full penetrance. The evidence for this variant shows: No data on healthy adult observations. Therefore, this criterion is not applied due to absence of healthy individual data.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: Use when a variant rescues both an ATM specific feature and radiosensitivity. The evidence for this variant shows: No functional rescue studies. Therefore, this criterion is not applied because functional data are lacking.
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 studies. Therefore, this criterion is not applied due to missing family data.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: Missense variant in a gene for which primarily truncating variants are known to cause disease. The evidence for this variant shows: ATM has known pathogenic missense variants. Therefore, this criterion is not applied because missense is a recognized mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: Use ATM PM3/BP2 table for cis observations. The evidence for this variant shows: No data on cis/trans allele configuration. Therefore, this criterion is not applied due to lack of allelic phase information.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: In-frame deletions/insertions in repetitive regions without known function. The evidence for this variant shows: Y2954C is a missense change outside of repetitive region. Therefore, this criterion is not applied because variant type does not match.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: Protein analysis: REVEL ≤.249 or RNA analysis shows impact on splicing for benign. The evidence for this variant shows: REVEL = 0.90 and no splicing impact. Therefore, this criterion is not applied because computational evidence supports deleterious effect.
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 conflicting molecular diagnosis. Therefore, this criterion is not applied due to lack of alternate cause.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: Reputable source reports variant as benign. The evidence for this variant shows: ClinVar entries are all VUS. Therefore, this criterion is not applied because no authoritative benign assertion exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: Synonymous or deep intronic variant with no predicted splice impact. The evidence for this variant shows: Y2954C is missense. Therefore, this criterion is not applied because variant is not synonymous or intronic.