11-108289623-C-T

Variant names:

• chr11-108289623-C-T
• rs1800058
• NM_000051.4:c.4258C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.4258C>T​(p.Leu1420Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,605,174 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.017 (249 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: 0.809

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=0.0078905225).
• BP6: Variant 11-108289623-C-T is Benign according to our data. Variant chr11-108289623-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108289623-C-T is described in Lovd as [Benign]. Variant chr11-108289623-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1720/152268) while in subpopulation NFE AF= 0.0186 (1266/67990). AF 95% confidence interval is 0.0178. There are 16 homozygotes in gnomad4. There are 792 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.4258C>T	p.Leu1420Phe	missense_variant	Exon 29 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4258C>T	p.Leu1420Phe	missense_variant	Exon 29 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1720 AN: 152150 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.0110 AC: 2715 AN: 245854 Hom.: 18 AF XY: 0.0114 AC XY: 1516 AN XY: 133066

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00154

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00625

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.00992

GnomAD4 exome AF: 0.0167 AC: 24336 AN: 1452906 Hom.: 249 Cov.: 31 AF XY: 0.0165 AC XY: 11933 AN XY: 721996

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.00155

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00768

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0199

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0113 AC: 1720 AN: 152268 Hom.: 16 Cov.: 32 AF XY: 0.0106 AC XY: 792 AN XY: 74452

Gnomad4 AFR AF: 0.00346

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.00933

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0157 Hom.: 61

Bravo AF: 0.0108

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.0178 AC: 153

ExAC AF: 0.0120 AC: 1461

Asia WGS AF: 0.00202 AC: 8 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:25 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10 Other:1

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 15, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jul 15, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Feb 20, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 23, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Ataxia-telangiectasia syndrome Benign:4

Oct 05, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 07, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Leu1420Phe variant was identified in 81 of 4298 proband chromosomes (frequency: 0.02) from English, French, Dutch, American Indian/Non-Indian, Australian and North American individuals or families with familial and primary breast cancers, AT disease, CML, and individuals undergoing radiation therapy and was present in 108 of 6302 control chromosomes (frequency: 0.02) from healthy individuals (Johnson 2007 , LaPaglia 2010, Broeks 2008, Melo 2001, Petereit 2013, Renwick 2006, Li 2000, Thompson 2005, ). In 2 population-based, case-control studies, the variant was found not to increase breast cancer risk (Einarsdottir 2006, Thompson 2005). The variant was also identified in dbSNP (ID: rs1800058) as “other”, ClinVar (classified as conflicting interpretations of pathogenicity: classified benign by GeneDx, Div of Genomic Diagnostics, Children's Hospital of Philadelphia, Vantari Genetics, Prevention Genetics, Emory Genetics, Color Genomics Inc., Invitae; likely benign by Genetic Services Laboratory, U of Chicago; uncertain significance by Ambry Genetics; and unclassified by ITMI), Clinvitae (5X), LOVD 3.0 (2X), ATM-LOVD (1x). The variant was not identified in GeneInsight-COGR, Cosmic and MutDB. The variant was identified in control databases in 3069 (22 homozygous) of 272226 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 2316 of 124884 chromosomes (freq: 0.019), European (Finnish) in 279 of 25640 chromosomes (freq: 0.011), Other in 67 of 6316 chromosomes (freq: 0.011). The p.Leu1420 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

May 17, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.83	T;.;T
MetaRNN	Benign	0.0079	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.071	T;T;D
Sift4G	Benign	0.061	T;T;D
Polyphen		0.15	B;B;.
Vest4		0.22
MPC		0.17
ClinPred		0.020	T
GERP RS		-0.47
Varity_R		0.089
gMVP		0.53

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: rs1800058; hg19: chr11-108160350; COSMIC: COSV53729512; COSMIC: COSV53729512;