ATM c.1010G>A, p.Arg337His
NM_000051.4:c.1010G>A
COSMIC ID: COSM1158322, COSM21301
Likely Pathogenic
No ACMG/AMP or VCEP criteria are met for pathogenic or benign classification for NM_000051.4:c.1010G>A (R337H) in ATM. In the absence of supportive or contradictory evidence, the variant remains classified as a Variant of Uncertain Significance.
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.1010G>A
Protein Change
R337H
Location
Exon 8
(Exon 8 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 337: R337C
Alternate Identifiers
COSM1158322, COSM21301
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.1010G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00796%
Rare
Highest in Population
European (non-Finnish)
0.0123%
Low Frequency
Global: 0.00796%
European (non-Finnish): 0.0123%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251160Alt: 20Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00796%, 20/251160 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.0123%, 14/113538 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 18 submitter reviews in ClinVar
Submitter Breakdown
13 VUS
4 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Fibroblasts homozygous for this variant had normal radiation sensitivity, however, further studies are required to determine the global effect of this variant on ATM protein function (PMID: 30425284).
This missense variant replaces arginine with histidine at codon 337 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 individuals affected with breast cancer (PMID: 20305132, 23555315, 25186627, 29522266, 30303537, 33471991) or prostate cancer (PMID: 33436325), but also in control individuals (PMID: 23555315, 30303537, 33471991). This variant has been identified in 20/251160 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.
Variant summary: ATM c.1010G>A (p.Arg337His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 271398 control chromosomes (gnomAD and publications). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. c.1010G>A has been reported in the literature in individuals affected with Breast Cancer and other tumor phenotypes, including prostate cancer and pediatric retinoblastoma (e.g. Bernstein_2010, Zhang_2015, Tung_2015, Decker_2017, Hauke_2018, Girard_2019, Karlsson_2021, Dorling_2021), but was also found in healthy controls (e.g. Tiao_2017, Girard_2019, Dorling_2021, and in three women older than 70 years of age who have never had cancer, in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 25882375, 24356096, 20305132, 28779002, 22529920, 30303537, 29522266, 30814645, 28652578, 25186627, 26580448, 33436325, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=7), likely benign (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (13 clinical laboratories) and as Benign (1 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Likely benign (4 clinical laboratories).
COSMIC ID
COSM1158322, COSM21301
Recurrence
37 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
80
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (80 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 337: R337C
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.379
0.379
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: 5.68metasvm: 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 Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength." The evidence for this variant shows: NM_000051.4:c.1010G>A is a missense change and does not predict a null allele. Therefore, this criterion is not applied because the variant does not result in loss-of-function.
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. Use ATM PS1 Splicing table for splicing variants." The evidence for this variant shows: no other variant causes the same Arg337His amino acid change. Therefore, this criterion is not applied because there is no established pathogenic variant with the same amino acid 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 de novo data are available. 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 is: "Moderate Strength: 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 functional data are lacking.
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 controls (case-control studies)." The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied due to absence of statistical association studies.
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: Arg337 is not in the characterized ATM kinase domain or known hotspot and recurrence in COSMIC is zero. Therefore, this criterion is not applied because the variant does not reside in a recognized critical domain or hotspot.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Frequency ≤0.001% if n=1 in a single subpopulation." The evidence for this variant shows: MAF in gnomAD is 0.00796%, exceeding the ≤0.001% threshold. Therefore, this criterion is not applied because the variant is not sufficiently rare by VCEP frequency cutoffs.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive occurrences." The evidence for this variant shows: no data on trans occurrences with a pathogenic allele. Therefore, this criterion is not applied due to lack of recessive inheritance evidence.
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 variants." The evidence for this variant shows: R337H is a missense change and does not alter protein length. Therefore, this criterion is not applied because it does not involve a length change.
PM5
PM5 (Not Applied) 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 for this variant shows: no pathogenic variant at residue Arg337 has been reported. Therefore, this criterion is not applied because there is no precedent of a pathogenic missense at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of maternity and paternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
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 are available. Therefore, this criterion is not applied because family studies are lacking.
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 is a common mechanism of disease." The evidence for this variant shows: ATM has a moderate rate of tolerated missense variation. Therefore, this criterion is not applied because gene-specific context does not support it.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: REVEL >0.7333; RNA: At least one well-established in silico predictor shows impact on splicing." The evidence for this variant shows: REVEL score is 0.38 and SpliceAI is 0.03, neither meeting thresholds. Therefore, this criterion is not applied because computational predictions do not support a 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 phenotype specificity data are provided. Therefore, this criterion is not applied due to lack of clinical correlation.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar entries are conflicting (VUS, benign, likely benign). Therefore, this criterion is not applied because no reputable consensus on pathogenicity exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases (Stand Alone Benign)." The evidence for this variant shows: MAF is 0.00796%, well below 5%. Therefore, this criterion is not applied because the allele frequency is not in the benign range.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: MAF of 0.00796% does not exceed expected thresholds. Therefore, this criterion is not applied because frequency is not unexpectedly high.
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 disease with full penetrance expected at an early age." The evidence for this variant shows: no such 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: "Moderate Strength: Use when a variant rescues both an ATM-specific feature AND radiosensitivity." The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied because functional assays 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 data. Therefore, this criterion is not applied due to insufficient family studies.
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 disease mechanism includes both missense and truncating variants. Therefore, this criterion is not applied because missense is a recognized disease mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table for cases in trans with a pathogenic variant." The evidence for this variant shows: no trans data with pathogenic allele. Therefore, this criterion is not applied due to lack of cis/trans information.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function." The evidence for this variant shows: R337H is a missense substitution. Therefore, this criterion is not applied because the variant is not an in-frame indel.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Protein Analysis: REVEL ≤0.249; RNA: at least one predictor shows impact on splicing." The evidence for this variant shows: REVEL is 0.38 and SpliceAI is 0.03, not meeting thresholds. Therefore, this criterion is not applied because computational evidence does not support a benign effect under VCEP cutoffs.
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 alternate cause documented. Therefore, this criterion is not applied due to lack of evidence of an alternate diagnosis.
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." The evidence for this variant shows: ClinVar submissions are conflicting with no clear consensus. Therefore, this criterion is not applied because no single reputable source consensus exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no impact on splicing and located outside conserved splice sites." The evidence for this variant shows: R337H is a missense change. Therefore, this criterion is not applied because the variant is not synonymous.