11-108289740-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000051.4(ATM):​c.4375G>A​(p.Gly1459Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,613,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

7
9
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:1

Conservation

PhyloP100: 6.59
Variant links:
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.4375G>A p.Gly1459Arg missense_variant Exon 29 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.4375G>A p.Gly1459Arg missense_variant Exon 29 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
251208
Hom.:
0
AF XY:
0.0000663
AC XY:
9
AN XY:
135774
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000968
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000174
AC:
254
AN:
1461408
Hom.:
0
Cov.:
31
AF XY:
0.000175
AC XY:
127
AN XY:
726992
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000208
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000202
Hom.:
0
Bravo
AF:
0.000140
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:17Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Jan 15, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with leukemia, breast cancer, and Lynch-syndrome associated cancers and/or polyps but also in healthy controls (PMID: 17623063, 19781682, 25980754, 26580448, 26976419, 28652578, 28779002, 29458332, 30374176, 33471991); This variant is associated with the following publications: (PMID: 19781682, 26976419, 28779002, 25980754, 17623063, 29458332, 30374176, 26580448, 28652578, 33436325, 35098669, 33471991) -

Apr 11, 2023
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Computational tools predict that this variant is damaging. -

Jul 23, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Uncertain:4
Nov 28, 2023
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G1459R variant (also known as c.4375G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4375. The glycine at codon 1459 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in individuals diagnosed with breast cancer and healthy controls across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Decker B et al. J. Med. Genet. 2017 Nov;54:732-741; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Edvardsen H et al. Radiat Oncol. 2007 Jul;2:25). 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. -

Aug 06, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 27, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 1459 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in individuals affected with breast cancer (PMID: 17623063, 26976419, 28779002, 33471991), prostate cancer (PMID: 33436325), colorectal cancer (PMID: 29458332), an individual suspected of Lynch syndrome (PMID: 25980754), and in healthy controls (PMID: 19781682, 28779002, 33471991). This variant has also been identified in 16/282612 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. -

Ataxia-telangiectasia syndrome Uncertain:3
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1459 of the ATM protein (p.Gly1459Arg). This variant is present in population databases (rs145667735, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 17623063, 25980754, 26976419, 29458332, 30374176, 33436325). ClinVar contains an entry for this variant (Variation ID: 127387). 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. -

Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 14, 2024
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ATM c.4375G>A (p.Gly1459Arg) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified Uncertain:2
Aug 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ATM c.4375G>A (p.Gly1459Arg) 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 5.1e-05 in 256006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.1e-05 vs 0.001), allowing no conclusion about variant significance. c.4375G>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast/colorectal/pediatric and other cancers (example, Edvardsen_2007, Tung_2016, Yurgelun_2015, Dominguez-Valentin_2018, Zhang_2015, Tsai_2019) but also in controls (example, Tavtigian_2009, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. At-least one co-occurrence with another pathogenic variant has been reported (BRCA2 variant not specified, Tsai_2019). 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: 29458332, 17623063, 19781682, 30374176, 26976419, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127387). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1Benign:1
May 17, 2024
Myriad Genetics, Inc.
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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]. -

Mar 21, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Apr 25, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1
Aug 01, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ATM c.4375G>A variant is predicted to result in the amino acid substitution p.Gly1459Arg. This variant has been documented in individuals with suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Dominguez-Valentin et al. 2018. PubMed ID: 29458332), breast cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Additional File 1, Edvardsen et al. 2007. PubMed ID: 17623063), and prostate cancer (Table S4, Karlsson et al. 2021. PubMed ID: 33436325). However, Tavtigian et al. has observed this variant only in the control group in a large case-control-based study on breast cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108160467-G-A). In ClinVar, it is classified as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127387/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome Uncertain:1
Oct 19, 2018
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) that results in a glycine to arginine amino acid change at residue 1459 in the ATM protein. This is a previously reported variant (ClinVar) that has been observed in at least one breast cancer patient (PMID 26976419), two patients being tested for Lynch syndrome (PMID 25980754), a patient with familial colorectal cancer (PMID 29458332), and one healthy control with no cancer (PMID 19781682). This variant is rare in control population datasets (gnomAD database, 16/276984 alleles, .006% overall frequency). A meta-analysis in breast cancer patients did not identify any enrichment of this variant in breast cancer cases versus healthy controls (PMID 19781682). The Gly1459 residue is not located in a known functional domain, and studies assessing the effect of this variant on ATM function are not published in the literature, to our knowledge. However, multiple in silico tools queried predict that this glycine to arginine amino acid change would be damaging. The glycine at this position is highly evolutionarily conserved across mammalian species examined. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider the significance of this variant to be uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.30
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.36
T;T;T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;.;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.75
D;D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Uncertain
2.5
M;M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-4.3
D;D;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0030
D;D;T
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.59
MutPred
0.53
Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);.;
MVP
0.93
MPC
0.17
ClinPred
0.52
D
GERP RS
5.6
Varity_R
0.52
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145667735; hg19: chr11-108160467; COSMIC: COSV53749228; COSMIC: COSV53749228; API