ATM c.1688T>G, p.Met563Arg
NM_000051.4:c.1688T>G
Variant of Uncertain Significance (VUS)
NM_000051.4:c.1688T>G (M563R) is classified as a Variant of Uncertain Significance. Only PM5 and BP4 apply at Supporting strength, yielding conflicting evidence insufficient for a definitive pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM5
BP4
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.1688T>G
Protein Change
M563R
Location
Exon 11
(Exon 11 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 563: M563I, M563I, M563I
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.1688T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000707%
Very Rare
Highest in Population
African/African American
0.00401%
Rare
Global: 0.000707%
African/African American: 0.00401%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282688Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000707%, 2/282688 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00401%, 1/24968 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
8 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The p.M563R variant (also known as c.1688T>G), located in coding exon 10 of the ATM gene, results from a T to G substitution at nucleotide position 1688. The methionine at codon 563 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This missense variant replaces methionine with arginine at codon 563 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28779002). This variant has been identified in 2/282688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (8 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
ClinVar reports other pathogenic variants at position 563: M563I, M563I, M563I
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.066
0.066
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: 0.87polyphen_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, the rule for PVS1 is: 'Use ATM PVS1 Decision Tree at Very Strong strength to evaluate null variants in ATM.' The evidence shows NM_000051.4:c.1688T>G is a missense variant (M563R), not a null variant. Therefore, this criterion is not applied.
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 shows M563R is a novel amino acid change not identical to any previously established pathogenic variant. Therefore, this criterion 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.' No de novo occurrence has been documented for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 is gene-specific and requires functional studies demonstrating a deleterious effect on ATM-specific features or radiosensitivity. No functional characterization exists for M563R. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Case-control studies; p-value ≤ .05 and odds ratio ≥ 2.' No case-control or proband frequency data are available. Therefore, this criterion 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 position of M563R is not within a recognized functional domain or hot spot of ATM. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Frequency ≤ 0.001% if n=1 in a single sub population.' The variant has a frequency of 0.00401% in the African population and two alleles in gnomAD, exceeding the threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive occurrences.' There is no evidence of this variant in trans with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Use for stop-loss variants.' M563R does not result in stop-loss or protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence shows a pathogenic missense variant previously reported at residue 563. Therefore, this criterion is applied at Supporting strength.
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.' No data suggest de novo occurrence. Therefore, this criterion 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, this criterion 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 variants and where missense is a common mechanism of disease.' ATM tolerates diverse missense variants and this criterion does not apply. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Protein: REVEL > 0.7333; RNA: at least one predictor shows impact.' The REVEL score is 0.07 and SpliceAI is low. Therefore, this criterion 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 provided. Therefore, this criterion 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 evidence.' The variant is reported as VUS in ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Allele frequency > 0.5%.' The variant frequency is 0.00401%, well below this threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Filtering Allele Frequency > 0.05%.' The frequency is 0.00401%, below this threshold. Therefore, this criterion 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 observation is reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Use when a variant rescues ATM-specific features.' No functional rescue data are available. Therefore, this criterion is not applied.
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.' No segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease.' ATM has pathogenic missense variants; thus BP1 does not apply. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for recessive occurrences.' No evidence of trans configuration with a pathogenic variant. Therefore, this criterion 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 region without known function.' Not applicable to this missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Protein Analysis: Metapredictor REVEL score ≤ .249; RNA: at least one predictor shows impact.' The REVEL score is 0.07 and SpliceAI shows no impact. Therefore, this criterion is applied at Supporting strength.
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 alternate basis is reported. Therefore, this criterion 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 evidence.' No such report exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no splicing impact.' The variant is missense. Therefore, this criterion is not applied.