rs147915571

chr11-108244066-G-Achr11-108244066-G-Cchr11-108244066-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000051.4(ATM):c.610G>A(p.Gly204Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000799 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G204V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:3 O:1
• Conservation: PhyloP100: 5.30

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10439274).
• BP6: Variant 11-108244066-G-A is Benign according to our data. Variant chr11-108244066-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127419.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=15, Likely_benign=3, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.610G>A	p.Gly204Arg	missense_variant	6/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.610G>A	p.Gly204Arg	missense_variant	6/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151868 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 251150 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1461566 Hom.: 0 Cov.: 34 AF XY: 0.0000756 AC XY: 55 AN XY: 727074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000836

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000790 AC: 12 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74280

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 18, 2023	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 disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 24356096, 27720647, 26580448, 26837699, 28873162, 29470806, 29522266, 25186627, 20305132, 33436325, 34204722, 30303537, 30306255, 28652578, 33471991, 34250389, 31206626, 36685941) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 18, 2023	The frequency of this variant in the general population, 0.00023 (8/35374 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with breast and/or ovarian cancer (PMIDs: 34204722 (2021), 31206626 (2019), 29470806 (2018), 29522266 (2018), 30306255 (2018), 28779002 (2017), 25186627 (2015), 20305132 (2010)), lymphocytic leukemia (PMIDs: 28652578 (2017), 26837699 (2016)), rhabdomyosarcoma (PMID: 26580448 (2015)), and prostate cancer (PMID: 33436325 (2021). The variant has also been observed in healthy controls (PMIDs: 33436325 (2021), 30303537 (2019), 31206626 (2019), 28652578 (2017), 28779002 (2017)). In an individual with breast cancer, this variant co-occurred with a pathogenic variant in the BRCA1 gene, suggesting it may not be the cause of disease (PMID: 25186627 (2015)). 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2023	This missense variant replaces glycine with arginine at codon 204 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 20305132, 25186627, 28779002, 29470806, 29522266, 34204722), chronic lymphocytic leukemia (PMID: 26837699, 28652578), and in unaffected controls (PMID: 28652578). In a large international case-control study, this variant was reported in 9/60457 breast cancer cases and 8/53453 controls (OR=0.995, 95%CI 0.384 to 2.578, p-value=1; PMID: 33471991). This variant has also been identified in 29/282440 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 05, 2022	The p.G204R variant (also known as c.610G>A), located in coding exon 5 of the ATM gene, results from a G to A substitution at nucleotide position 610. The glycine at codon 204 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in ethnically diverse cohorts of breast, ovarian, prostate, and/or chronic lymphocytic leukemia patients, as well as healthy controls (Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Singh J et al. Breast Cancer Res. Treat. 2018 Jul; Dorling et al. N Engl J Med. 2021 02;384:428-439; 170:189-196; Weitzel JN et al. Cancer, 2019 08;125:2829-2836; Karlsson Q et al. Eur Urol Oncol. 2021 08;4:570-579; Nadeu F et al. Blood. 2016 04;127:2122-30). This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with rhabdomyosarcoma (Zhang J et al. N Engl J Med. 2015 Dec;373:2336-2346). This amino acid position is well 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. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: ATM c.610G>A (p.Gly204Arg) 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 0.00011 in 251150 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. c.610G>A has been reported in the literature in individuals affected with breast and/or ovarian cancer, prostate cancer, chronic lymphocytic leukemia and rhabdosarcoma in settings of multigene panel testing and in unaffected control cohorts (example, Tung 2015, Decker 2017, Singh 2018, Nadeu 2016, Tiao 2017, Zhang 2015, Bonache_2018, Girard_2019, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia or Breast Cancer. At-least one co-occurrence with another pathogenic variant has been reported in an individual undergoing multigene panel testing for breast cancer (BRCA1 c.5172dupA, p.Glu1725Argfs*7, Tung_2015), providing supporting evidence for a benign role. A recent study that included this variant reports that carriers of loss of function variants in the ATM gene have a significantly higher risk of developing breast cancer than carriers of an ATM missense variant (OR for LOF =17.4; OR for missense = 1.6) (Girard_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters have assessed the variant since 2014: nine have classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Familial cancer of breast Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 17, 2023	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]. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 23, 2022

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ATM-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

The ATM c.610G>A variant is predicted to result in the amino acid substitution p.Gly204Arg. This variant has been reported in an individual with chronic lymphocytic leukemia (Supplementary Table S8, Nadeu et al. 2016. PubMed ID: 26837699) and in individuals with ATM associated hereditary cancers such as breast and/or ovarian cancer (Supplementary Table S1, Hauke et al. 2018. PubMed ID: 29522266; Supplementary Table S3, Singh et al. 2018. PubMed ID: 29470806). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127419/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 05-06-2016 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;N;D;N
REVEL	Benign	0.11
Sift	Benign	0.46	T;T;D;T
Sift4G	Uncertain	0.011	D;T;D;T
Polyphen		0.91	.;P;.;P
Vest4		0.60, 0.55
MutPred		0.34		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);
MVP		0.85
MPC		0.40
ClinPred		0.23	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.57

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

Other links and lift over

dbSNP: rs147915571; hg19: chr11-108114793; COSMIC: COSV99069705;