rs1801516

chr11-108304735-G-Achr11-108304735-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):c.5557G>A(p.Asp1853Asn) variant causes a missense change. The variant allele was found at a frequency of 0.13 in 1,613,666 control chromosomes in the GnomAD database, including 15,385 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1853V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1205 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14180 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 5.93

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014446676).
• BP6: Variant 11-108304735-G-A is Benign according to our data. Variant chr11-108304735-G-A is described in ClinVar as [Benign]. Clinvar id is 128458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108304735-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5557G>A	p.Asp1853Asn	missense_variant	37/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5557G>A	p.Asp1853Asn	missense_variant	37/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16174 AN: 152020 Hom.: 1205 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.114 AC: 28505 AN: 250874 Hom.: 2083 AF XY: 0.116 AC XY: 15745 AN XY: 135594

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.0612

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00632

Gnomad SAS exome AF: 0.0772

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.133 AC: 193944 AN: 1461528 Hom.: 14180 Cov.: 33 AF XY: 0.132 AC XY: 95950 AN XY: 727062

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.0646

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.00313

Gnomad4 SAS exome AF: 0.0775

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.143

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.106 AC: 16176 AN: 152138 Hom.: 1205 Cov.: 32 AF XY: 0.108 AC XY: 8064 AN XY: 74354

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.0906

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.0758

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.103

Alfa AF: 0.130 Hom.: 2922

Bravo AF: 0.0928

TwinsUK AF: 0.140 AC: 518

ALSPAC AF: 0.148 AC: 572

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.140 AC: 1205

ExAC AF: 0.110 AC: 13333

Asia WGS AF: 0.0370 AC: 130 AN: 3476

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Ataxia-telangiectasia syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25591549, 31382929, 28652578, 18502988, 24728327, 16914028, 27599564, 27153395, 17333338, 15756685, 22792358, 22529920, 20396981, 18465141, 17517479, 23585524, 24599715, 19147782, 17351744) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 12, 2017	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 12, 2015	This alteration is classified as 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;.
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.000051	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	0.20	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.044	B;B
Vest4		0.31
MPC		0.13
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.44
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1801516; hg19: chr11-108175462; COSMIC: COSV53728020; COSMIC: COSV53728020;