11-108272572-A-G

Position:

• chr11-108272572-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2_Strong BA1 BP4

This summary comes from the ClinGen Evidence Repository: The ATM c.3118A>G (p.Met1040Val) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.2% (AFR) which is above the ATM BA1 threshold of 0.5% (BA1). This variant has been observed in a homozygous state in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). In silico protein predictors (BayesDel, score:-0.45, AGVGD, Class C0) predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA151920/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:27 O:1
• Conservation: PhyloP100: 0.350

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 -13 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3118A>G	p.Met1040Val	missense_variant	21/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3118A>G	p.Met1040Val	missense_variant	21/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1740 AN: 152220 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00307 AC: 772 AN: 251290 Hom.: 18 AF XY: 0.00225 AC XY: 305 AN XY: 135838

Gnomad AFR exome AF: 0.0426

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00112 AC: 1640 AN: 1461446 Hom.: 30 Cov.: 32 AF XY: 0.000949 AC XY: 690 AN XY: 727044

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.0114 AC: 1744 AN: 152338 Hom.: 37 Cov.: 32 AF XY: 0.0111 AC XY: 824 AN XY: 74500

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00209 Hom.: 7

Bravo AF: 0.0132

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:11 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Met1040Val variant was identified in 18 of 1214 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer or non-Hodgkin lymphoma (Thorstenson 2001, Bretsky 2003, Sipahimalani 2007). The variant was also identified in ClinVar (benign 4x: GeneDx, Ambry Genetics, Invitae, Prevention Genetics; likely benign 3x: Mercy Hospital, Illumina, University of Chicago; not provided 1x: ITMI) unconfirmed somatic 1x: OMIM), COSMIC (2 lymphoid neoplasms, somatic status unknown), MutDB (link to UniProtKB/Swiss-Prot database, variant is unclassified with poor conservation across species), databases. The variant was not identified in the GeneInsight-COGR, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1095 (27 homozygous) of 277102 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 1012 of 24020 chromosomes (freq: 0.042). The p.Met1040Val residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, and HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 19, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2016	Variant summary: The ATM c.3118A>G (p.Met1040Val) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 459/122598 control chromosomes (10 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0413846 (428/10342, 10 homozygotes). This frequency is about 10 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Variant has been reported by multiple studies in both patients and healthy controls, supporting the non-pathogenic nature of this variant. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Considering the high allele frequency of the variant and the homozygous occurrences in the African subpopulation, it was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -

Ataxia-telangiectasia syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Familial cancer of breast Benign:2

Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.3118A>G (p.Met1040Val) variant has a GnomAD (v2.1.1) filtering allele frequency of 4.2% (AFR) which is above the ATM BA1 threshold of 0.5% (BA1). This variant has been observed in a homozygous state in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 500031, 61756). In silico protein predictors (BayesDel, score:-0.45, AGVGD, Class C0) predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 13, 2024	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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]. -

B-cell non-Hodgkin lymphoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1997

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 16, 2020

- -

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	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.4
DANN	Benign	0.35
DEOGEN2	Benign	0.045	.;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T;T;.
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.096
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.083, 0.10
MVP		0.65
MPC		0.13
ClinPred		0.0014	T
GERP RS		-1.1
Varity_R		0.12
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3092857; hg19: chr11-108143299; COSMIC: COSV53737085; COSMIC: COSV53737085;