ATM c.200A>G, p.Tyr67Cys
NM_000051.4:c.200A>G
Variant of Uncertain Significance (VUS)
This ATM Y67C variant remains a VUS. Only PM2_supporting (absent from population databases) is met per VCEP criteria; no additional pathogenic or benign criteria apply, and evidence is insufficient to shift classification.
ACMG/AMP Criteria Applied
PM2
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.200A>G
Protein Change
Y67C
Location
Exon 4
(Exon 4 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 67 in gene ATM
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.200A>G
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
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
9 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The p.Y67C variant (also known as c.200A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 200. The tyrosine at codon 67 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also identified in a patient with autoimmune lymphoproliferative syndrome (ALPS) -like phenotype (Grossi A et al. Genes (Basel), 2021 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 (9 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 67 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.26
0.26
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
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.74metasvm: 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, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows it is a missense change (Y67C) rather than a null variant. Therefore, this criterion is Not Applied because PVS1 applies only to predicted loss-of-function variants.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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 previously established pathogenic variant resulting in the same Y67C amino acid change. Therefore, PS1 is Not Applied.
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." There are no data on confirmed de novo occurrence. Therefore, PS2 is Not Applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (Supporting) is: "Supporting Strength: Supporting Use when a variant fails to rescue an ATM specific feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency." There are no functional studies of Y67C. Therefore, PS3 is Not Applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5)." No case-control or cohort data are available. Therefore, PS4 is Not Applied.
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 variant lies in a region without documented mutational hot spot or critical domain annotation for ATM. Therefore, PM1 is Not Applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply." The evidence shows the variant is absent from gnomAD and other population databases (MAF = 0%). Therefore, PM2 is Applied at Supporting strength because the variant meets the VCEP rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Very Strong Strength: Very Strong Use ATM PM3/BP2 table. ..." The evidence shows no data on allelic configuration in a recessive context. Therefore, PM3 is Not Applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Moderate Use for stop-loss variants." This is a missense variant without alteration of protein length. Therefore, PM4 is Not Applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047..." This variant is missense and there is no different pathogenic missense at the same codon. 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 of paternity and maternity." There are no de novo data. Therefore, PM6 is Not Applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation 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, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common disease mechanism." ATM has both truncating and missense pathogenic variants; this criterion is not specifically met. Therefore, PP2 is Not Applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing." The evidence shows REVEL = 0.26 (<0.7333) and SpliceAI predicts no impact. Therefore, PP3 is Not Applied.
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." 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: "Reputable source reports variant as pathogenic without available evidence." ClinVar reports VUS and likely benign; no unanimous pathogenic. Therefore, PP5 is Not Applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The variant frequency is 0%. Therefore, BA1 is Not Applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong Filtering Allele Frequency >.05%." The variant frequency is 0%. Therefore, BS1 is Not Applied.
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 expected at an early age." No such data exist. Therefore, BS2 is Not Applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Moderate Strength: Moderate Use when a variant rescues both an ATM specific feature and radiosensitivity." 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: "Non-segregation or lack of segregation in affected members of a family." No segregation data are available. Therefore, BS4 is Not Applied.
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 pathogenic." ATM has known pathogenic missense variants. Therefore, BP1 is Not Applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Strong Strength: Strong Use ATM PM3/BP2 table." No evidence of in trans occurrence with a pathogenic variant. 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 without a known function." This is a missense change. Therefore, BP3 is Not Applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting Protein Analysis: Metapredictor REVEL score ≤.249; RNA: at least one well-established in silico predictor shows impact on splicing." The evidence shows REVEL = 0.26 (>0.249) and SpliceAI predicts no impact on splicing. Therefore, BP4 is Not Applied.
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." No such evidence is present. Therefore, BP5 is Not Applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." ClinVar submissions are conflicting and not uniformly benign. Therefore, BP6 is Not Applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants." This is a missense variant. Therefore, BP7 is Not Applied.