ATM c.9031A>G, p.Met3011Val
NM_000051.4:c.9031A>G
COSMIC ID: COSM6005494
Variant of Uncertain Significance (VUS)
This missense variant is extremely rare in population databases and in silico predictions support benign impact (BP4), but lacks additional corroborating benign or pathogenic evidence, and therefore remains classified as a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
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.9031A>G
Protein Change
M3011V
Location
Exon 63
(Exon 63 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 3011 in gene ATM
Alternate Identifiers
COSM6005494
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.9031A>G
Active Tracks
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Clinical Data
Global Frequency
0.00389%
Rare
Highest in Population
European (non-Finnish)
0.00774%
Rare
Global: 0.00389%
European (non-Finnish): 0.00774%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282840Alt: 11Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00389%, 11/282840 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00774%, 10/129144 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 14 submitter reviews in ClinVar
Submitter Breakdown
13 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
The p.M3011V variant (also known as c.9031A>G), located in coding exon 62 of the ATM gene, results from an A to G substitution at nucleotide position 9031. The methionine at codon 3011 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in multiple individuals diagnosed with breast cancer (Teraoka SN et al. Cancer. 2001 Aug;92(3):479-87; Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46). Another study found this alteration in 1 of 270 breast and/or ovarian cancer families (Thorstenson YR et al. Cancer Res. 2003 Jun;63(12):3325-33). This alteration was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
The ATM c.9031A>G (p.Met3011Val) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 11505391 (2001), 12810666 (2003), 19781682 (2009)), glioblastoma (PMID: 26689913 (2015)), prostate cancer (PMID: 33436325 (2021)), and melanoma (PMID: 34262154 (2021)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000077 (10/129144 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Variant summary: ATM c.9031A>G (p.Met3011Val) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-05 in 251442 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in ATM, allowing no conclusion about variant significance. c.9031A>G has been reported in the literature in individuals affected with breast cancer (e.g. Tavtigian_2009, Teraoka_2001, Thorstenson_2003) and prostate cancer (e.g. Karlsson_2020) without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (APC c.487C>T, p.Gln163Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27200287, 30197789, 33436325, 26689913, 25148578, 19781682, 11505391, 12810666). ClinVar contains an entry for this variant (Variation ID: 181906). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3011 of the ATM protein (p.Met3011Val). This variant is present in population databases (rs372795527, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer, glioblastoma multiforme, prostate cancer, and pancreatic cancer (PMID: 11505391, 12810666, 19781682, 26689913, 33436325, 35047863). ClinVar contains an entry for this variant (Variation ID: 181906). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (13 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 3011 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.181
0.181
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: 3.22polyphen_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: 'Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows: NM_000051.4:c.9031A>G is a missense change (M3011V) and not a null variant. Therefore, this criterion is not applied because the variant does not meet any PVS1 null variant condition.
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: there is no previously established pathogenic variant with the same amino acid change at position M3011. Therefore, this criterion is not applied because the variant does not match any known pathogenic amino acid substitution.
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 data on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 (Moderate Strength) is: 'Moderate 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 because required functional assay evidence is missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (e.g., case-control data).'. The evidence for this variant shows: no case-control or proband counting data. Therefore, this criterion is not applied due to absence of statistical 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: M3011V is not reported in a known functional domain hotspot in ATM. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting Strength) is: 'Frequency ≤.001% if n=1 in a single sub population; n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply.'. The evidence for this variant shows: allele count is 11/282,840 (MAF=0.00389%), n>1 and >0.001%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 involves using the ATM PM3/BP2 table for recessive in trans observations. The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.'. The evidence for this variant shows: M3011V is a missense substitution and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 (Supporting Strength) is: 'Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...'. The evidence for this variant shows: M3011V is a missense change, not a truncating variant. Therefore, this criterion 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).'. The evidence for this variant shows: no parental relationship information. 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.'. The evidence for this variant shows: no familial segregation data. 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease.'. The evidence for this variant shows: ATM has a higher rate of tolerated missense and disease is typically caused by loss-of-function rather than missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (Supporting Strength) is: 'Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing.'. The evidence for this variant shows: REVEL=0.18 (<0.7333) and SpliceAI=0.04 (no splicing impact). 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.'. The evidence for this variant shows: no phenotype or clinical presentation 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.'. The evidence for this variant shows: ClinVar submissions are predominantly VUS with one Likely Benign; no reputable source labeled it pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 (Stand Alone Strength) is: 'Filtering Allele Frequency >.5%'. The evidence for this variant shows: MAF=0.00389% which is <<0.5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 (Strong Strength) is: 'Filtering Allele Frequency >.05%'. The evidence for this variant shows: MAF=0.00389% which is <0.05%. 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 (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age.'. The evidence for this variant shows: no healthy adult observation data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 (Moderate Strength) is: 'Use when a variant rescues both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.'. The evidence for this variant shows: no functional rescue data. 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.'. The evidence for this variant shows: 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 for which primarily truncating variants are known to cause disease.'. The evidence for this variant shows: ATM missense variants can be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 involves the ATM PM3/BP2 table for cis observations. The evidence for this variant shows: no data on cis with 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 a repetitive region without a known function.'. The evidence for this variant shows: M3011V is a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 (Supporting Strength) is: 'Supporting Protein Analysis: Metapredictor REVEL score ≤.249; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing; NOTE: Splice analysis needs to be considered for all variant types...'. The evidence for this variant shows: REVEL=0.18 (≤.249) and SpliceAI max=0.04 (no splicing impact). Therefore, this criterion is applied at Supporting strength because both protein and RNA computational predictors support a benign 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 such case data. 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.'. The evidence for this variant shows: ClinVar entries include one Likely Benign but not sufficient to be considered a well-established reputable source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site.'. The evidence for this variant shows: it is a missense, not synonymous. Therefore, this criterion is not applied.