rs79701258

chr11-108280980-T-A

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.3403-15T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 151,836 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (201 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (190 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.34

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 (BayesDel_noAF=-0.89).
• BP6: Variant 11-108280980-T-A is Benign according to our data. Variant chr11-108280980-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 136441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108280980-T-A is described in Lovd as [Benign]. Variant chr11-108280980-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3403-15T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3403-15T>A		splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4237 AN: 151718 Hom.: 202 Cov.: 31

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000692

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00956 AC: 2217 AN: 231976 Hom.: 71 AF XY: 0.00775 AC XY: 975 AN XY: 125826

Gnomad AFR exome AF: 0.0993

Gnomad AMR exome AF: 0.00625

Gnomad ASJ exome AF: 0.000219

Gnomad EAS exome AF: 0.00878

Gnomad SAS exome AF: 0.00916

Gnomad FIN exome AF: 0.000247

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00287

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00435 AC: 6109 AN: 1405244 Hom.: 190 Cov.: 28 AF XY: 0.00413 AC XY: 2890 AN XY: 700264

Gnomad4 AFR exome AF: 0.0952

Gnomad4 AMR exome AF: 0.00677

Gnomad4 ASJ exome AF: 0.000279

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.00890

Gnomad4 FIN exome AF: 0.000291

Gnomad4 NFE exome AF: 0.000766

Gnomad4 OTH exome AF: 0.00810

GnomAD4 genome AF: 0.0279 AC: 4243 AN: 151836 Hom.: 201 Cov.: 31 AF XY: 0.0268 AC XY: 1992 AN XY: 74250

Gnomad4 AFR AF: 0.0941

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0110

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.0000952

Gnomad4 NFE AF: 0.000707

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0237 Hom.: 16

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied by a panel of primary immunodeficiencies. Number of patients: 22. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2014	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. -

Ataxia-telangiectasia syndrome Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Sep 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 22, 2021

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM c.3403-15T>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, databases. The variant was identified in dbSBP (ID: rs79701258) as “With Likely benign allele,” ClinVar (as likely benign by Ilumina and as benign by GeneDx and Color Genomics), Clinvitae, and ATM-LOVD databases. The variant was identified in control databases in 3007 of 258930 chromosomes at a frequency of 0.011613 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the African population at a frequency greater than 1% in 2265 (109 homozygous) of 23444 chromosomes (freq: 0.097), and at lower frequencies in the following populations: Other in 29 of 5964 chromosomes (freq. 0.005), Latino in 198 (1 homozygous) of 31316 chromosomes (freq. 0.006), European (Non-Finnish) in 104 of 119980 chromosomes (freq. 0.0009), Ashkenazi Jewish in 1 of 9232 chromosomes (freq. 0.0001), East Asian in 158 of 18072 (freq. 0.0087), European (Finnish) in 8 of 24280 chromosomes (freq. 0.0003) and South Asian in 244 (1 homozygous) of 26642 chromosomes (freq. 0.009), increasing the likelihood this could be a low frequency benign variant. 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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.57
Dann	Benign	0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs79701258; hg19: chr11-108151707; COSMIC: COSV53725120;