rs149711770

Positions:

• chr11-108284405-G-A
• chr11-108284405-G-C
• chr11-108284405-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP2_Strong BP4 BS1

This summary comes from the ClinGen Evidence Repository: The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals without ataxia-telangiectasia (Internal laboratory contributions; BP2_strong). Multiple in silico protein predictors predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA242620/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:27 O:1
• Conservation: PhyloP100: 3.29

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 -9 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.
• BS1: 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.3925G>A	p.Ala1309Thr	missense_variant	26/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3925G>A	p.Ala1309Thr	missense_variant	26/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000685 AC: 172 AN: 251238 Hom.: 0 AF XY: 0.000744 AC XY: 101 AN XY: 135790

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00118 AC: 1718 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.00113 AC XY: 823 AN XY: 727136

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74430

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000778

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000618 AC: 75

EpiCase AF: 0.000981

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:10 Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 06, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 04-03-2019 by Lab or GTR ID Division of Clinical Laboratories Kingston General Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ATM: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2023	BS1, BP4 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2023	The ATM c.3925G>A; p.Ala1309Thr variant (rs149711770) is reported in the literature in individuals affected with various cancers, but without clear disease association (Broeks 2008, Dominguez-Valentin 2018, Momozawa 2018, Xie 2018). This variant is also reported in equal numbers of cases and controls (Tavtigian 2009, Yu 2021), and in at least one family in which the variant did not segregate with disease (Wang 2019). This variant is also reported in ClinVar (Variation ID: 127377), and is found in the general population with an overall allele frequency of 0.069% (194/282624 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.076). Based on available information, this variant is considered to be benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ataxia-telangiectasia syndrome Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2020	The ATM c.3925G>A (p.Ala1309Thr) missense variant has a frequency of 0.0006864 (194 of 282,624 alleles) in gnomAD v2.1.1 with a maximum frequency of 0.001209 (156 of 129,002) in the European non-Finnish subpopulation (BS1_Supporting, https://gnomad.broadinstitute.org/). The most frequent known pathogenic variants in this gene occur at maximal subpopulation frequencies of 0.05%, 0.039%, and 0.033%. Five of seven in silico tools predict a benign effect of this variant on protein function (BP4; https://pecan.stjude.cloud/variant/8471). This variant has been observed in several patients with breast cancer (PMID: 26976419, 17393301, 20305132) and Lynch syndrome (PMID: 25980754). However, case control studies indicate that the variant is observed in equal frequencies in control individuals, suggesting that the variant is not likely to be associated with disease (PMID: 30287823, 19781682, 21787400). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1_Supporting, BP4. -
Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Jan 20, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Dec 12, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 2018	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2016	- -
Uncertain significance, flagged submission	clinical testing	True Health Diagnostics	Sep 29, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 20, 2021	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2020	Variant summary: ATM c.3925G>A (p.Ala1309Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 282624 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). In addition, in certain European subpopulations the variant was observed with an even higher occurrence, e.g. in the North-western European control population it occurred with a frequency of 0.0019, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Additionally, the variant was reported in 17/ 2559 European American women (i.e. with an allele frequency of 0.0015), who were older than age 70, and have never had cancer (in the FLOSSIES database); the allele frequency in this cohort is 1.5-fold higher than the MPAF (0.001), further supporting a benign role for the variant. The variant, c.3925G>A, has been reported in the literature in multiple individuals affected with Breast Cancer and other tumor phenotypes (without strong evidence for causality), and was also reported in controls, including a Swiss, non-cancer related cohort, where the variant was observed with an allele frequency of 0.005 (Kraemer_2019). In a large case-control study combined with meta-analysis, the variant was not associated with an increased risk for breast cancer (Tavtigian_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 15 other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (7x), likely benign (5x) or benign (3x). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2017	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, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial cancer of breast Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 15, 2024	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]. -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	Mar 09, 2022	The ATM c.3925G>A (p.Ala1309Thr) variant has a GnomAD (v2.1.1) filtering allele frequency of 0.1050% (NFE) which is above the ATM BS1 threshold of .05% (BS1). This variant has been observed in a homozygous and compound heterozygous state in multiple individuals without ataxia-telangiectasia (Internal laboratory contributions; BP2_strong). Multiple in silico protein predictors predict that this alteration is not deleterious (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 04, 2023	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, flagged submission

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Mar 09, 2018

This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid change at residue 1309 in the ATM protein. The variant is found at a frequency of 0.0062 (75/120390 alleles) in the Exome Aggregation Consortium database, with highest frequency among non-Finnish Europeans (0.00091, 61/66688 alleles). This residue (Ala1309) is not well conserved and is not found in a protein functional domain. In silico computational tools are inconclusive in their predictions on effects on protein structure and function. In a breast cancer case-control study (PMID: 19781682), the variant was found in 3/2531 cases and 3/2245 controls. These data indicate that this variant is not likely to be associated with disease, as it is found in equal frequencies in case and control populations. However, there is insufficient evidence to conclusively rule out any disease association. Thus, we consider this to be a variant of uncertain significance. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 11, 2023

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM p.Ala1309Thr variant was identified in 15 of 138364 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer and was present in 3 of 30056 control chromosomes (frequency: 0.0001) from healthy individuals (Broeks 2008, Tavtigian 2009, Balmana 2016, Bernstein 2010, Goldgar 2011, Momozawa 2018, Tung 2016, Young 2016). The variant was also identified in dbSNP (ID: rs149711770) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and five other submitters; and as uncertain significance by four submitters), and in LOVD 3.0 (3x as likely benign). The variant was identified in control databases in 191 of 276962 chromosomes at a frequency of 0.0007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 156 of 126510 chromosomes (freq: 0.001), African in 9 of 24028 chromosomes (freq: 0.0004), Other in 3 of 6460 chromosomes (freq: 0.0005), Latino in 6 of 34408 chromosomes (freq: 0.0002), East Asian in 15 of 18852 chromosomes (freq: 0.0008), Finnish in 2 of 25780 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish or South Asian populations. This variant was identified by our laboratory in a patient with a co-occurring pathogenic BRIP1 variant (c.133G>T, p.Glu45*), increasing the likelihood that the ATM p.Ala1309Thr variant does not have clinical significance. The p.Ala1309 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;T;.
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.7	.;M;M
MutationTaster	Benign	0.66	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Benign	0.076
Sift	Benign	0.084	T;T;T
Sift4G	Uncertain	0.054	T;T;T
Polyphen		0.0090	.;B;B
Vest4		0.17, 0.17
MVP		0.77
MPC		0.13
ClinPred		0.027	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.17

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: rs149711770; hg19: chr11-108155132; COSMIC: COSV53733128; COSMIC: COSV53733128;