11-108330281-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000051.4(ATM):c.7375C>T(p.Arg2459Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2459G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:16
• Conservation: PhyloP100: 1.33

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000051.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7375C>T	p.Arg2459Cys	missense_variant	50/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7375C>T	p.Arg2459Cys	missense_variant	50/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251258 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 22, 2013	The frequency of this variant in the general population, 0.000039 (5/129022 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021), 32658311 (2021), 29522266 (2018), 29752822 (2018)), prostate cancer (PMID: 33436325 (2021)), and in the somatic state in various cancers (PMIDs: 19018867 (2009), 23585524 (2013), 24983367 (2014)). It has also been described in unaffected individuals (PMID: 28652578 (2017)). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2023	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; This variant is associated with the following publications: (PMID: 28652578, 30099369, 23585524, 19018867, 27479817, 25742471, 24983367, 29522266, 28667006, 26010451, 29752822, 33436325, 34803902, 32658311, 23532176, 35365198, 33471991, 34284872) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ataxia-telangiectasia syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 26, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2459 of the ATM protein (p.Arg2459Cys). This variant is present in population databases (rs730881383, gnomAD 0.01%). This missense change has been observed in individual(s) with a high risk of breast, ovarian, or prostate cancer (PMID: 29522266, 29752822, 32658311, 33436325). ClinVar contains an entry for this variant (Variation ID: 185845). 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 (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 22, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 29, 2023	This missense variant replaces arginine with cysteine at codon 2459 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 29522266, 32658311, 33471991) and in an individual affected with chronic lymphocytic leukemia who also has a pathogenic ATM covariant (PMID: 19018867). This variant has also been observed in two healthy controls from a chronic lymphocytic leukemia case-control study (PMID: 28652578). This variant has been identified in 10/282668 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 12, 2022	The p.R2459C variant (also known as c.7375C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7375. The arginine at codon 2459 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358) as well as a cohort of Chinese breast cancer patients undergoing multigene panel testing (Li JY et al. Int. J. Cancer. 2019 01;144:281-289). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 12, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 19, 2020

Variant summary: ATM c.7375C>T (p.Arg2459Cys) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7375C>T has been reported in the literature in individuals affected with Breast Cancer and Chronic Lymphocytic Leukemia (e.g. Cejkova_2008, Navrkalova_2013, Li_2018, Hauke_2018, Ackay_2020), and healthy controls (e.g. Tiao_2017). 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. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Apr 18, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.41
MVP		0.96
MPC		0.31
ClinPred		0.71	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730881383; hg19: chr11-108201008; COSMIC: COSV53769970; COSMIC: COSV53769970;