11-108289005-C-T

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.4138C>T(p.His1380Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,613,616 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. H1380D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (86 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (232 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 0.100

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=0.0019094348).
• BP6: Variant 11-108289005-C-T is Benign according to our data. Variant chr11-108289005-C-T is described in ClinVar as [Benign]. Clinvar id is 133619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108289005-C-T is described in Lovd as [Likely_benign]. Variant chr11-108289005-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4138C>T	p.His1380Tyr	missense_variant	28/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4138C>T	p.His1380Tyr	missense_variant	28/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3251 AN: 152206 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0123 AC: 3100 AN: 251300 Hom.: 88 AF XY: 0.0125 AC XY: 1704 AN XY: 135816

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0150

Gnomad SAS exome AF: 0.0482

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00579 AC: 8456 AN: 1461292 Hom.: 232 Cov.: 31 AF XY: 0.00685 AC XY: 4978 AN XY: 726982

Gnomad4 AFR exome AF: 0.0715

Gnomad4 AMR exome AF: 0.00394

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0277

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.00825

GnomAD4 genome AF: 0.0213 AC: 3252 AN: 152324 Hom.: 86 Cov.: 32 AF XY: 0.0215 AC XY: 1604 AN XY: 74480

Gnomad4 AFR AF: 0.0668

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.0458

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00543 Hom.: 30

Bravo AF: 0.0230

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0709 AC: 312

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0145 AC: 1755

Asia WGS AF: 0.0330 AC: 117 AN: 3474

EpiCase AF: 0.000327

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24728327, 27153395, 27016235, 11505391, 11746755, 22529920, 20981092, 22995991) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.His1380Tyr variant was identified in 23 of 1184 proband chromosomes (frequency: 0.019) from individuals or families with CML, AML, ALL, Hodgkin disease and was present in 1 of 166 control chromosomes (frequency: 0.006) from healthy individuals (Melo 2001, Petereit 2013, Shi 2011, Takagi 2004). The variant was also identified in the following databases: dbSNP (ID: rs3092856) as other, ClinVar (classified as benign by Ambry Genetics, Prevention Genetics, Emory Genetics, Color Genomics, Invitae; classified as likely benign by Illumina), Cosmic (classified as Neutral (score 0.29), MutDB, and LOVD 3.0. The variant was not identified in the COGR, or ATM-LOVD. The variant was identified in control databases in 3636 (97 homozygous) of 277050 chromosomes at a frequency of 0.013 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 1625 of 24030 chromosomes (freq: 0.068), South Asian in 1484 of 30780 chromosomes (freq: 0.048), East Asian in 277 of 18862 chromosomes (freq: 0.015). The p.His1380 residue is not conserved in mammals and 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, HumanSpliceFinder) do not predict a difference in splicing. In study by Shi (2011), cases with ATM 4138CT variant presented with primary refractory disease, and ATM 4138C>T patients generally had inferior overall survival comparing with ATM 4138C>C patients. Results of a study by Takagi (2004) provide indirect evidence that H1380Y acts in a dominant-negative manner and H1380Y could be an allele with a very low penetrance. Patient with H1380Y exhibited normal p53 phosphorylation activity but defective c-Abl kinase activation. 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. -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 25, 2014	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
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. -

Ataxia-telangiectasia syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	Invitae	Feb 01, 2024	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 07, 2021

- -

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	0.053
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	13
Dann	Benign	0.70
DEOGEN2	Benign	0.084	T;T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T;.;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.11
MPC		0.14
ClinPred		0.00027	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3092856; hg19: chr11-108159732; COSMIC: COSV53753123; COSMIC: COSV53753123;