rs4986839

Positions:

• chr11-108353888-A-C
• chr11-108353888-A-G
• chr11-108353888-A-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.8786+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,604,136 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (57 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1143 hom.)
• Consequence: ATM NM_000051.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002930
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.222

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATM (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-108353888-A-C is Benign according to our data. Variant chr11-108353888-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 132696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108353888-A-C is described in Lovd as [Benign]. Variant chr11-108353888-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0246 (3740/152182) while in subpopulation NFE AF= 0.0377 (2565/68000). AF 95% confidence interval is 0.0365. There are 57 homozygotes in gnomad4. There are 1715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8786+8A>C		splice_region_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8786+8A>C		splice_region_variant, intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3742 AN: 152064 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0262 AC: 6577 AN: 251450 Hom.: 154 AF XY: 0.0267 AC XY: 3635 AN XY: 135894

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.0173

Gnomad ASJ exome AF: 0.0829

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0356 AC: 51622 AN: 1451954 Hom.: 1143 Cov.: 29 AF XY: 0.0348 AC XY: 25143 AN XY: 723064

Gnomad4 AFR exome AF: 0.00635

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0829

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0161

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0402

Gnomad4 OTH exome AF: 0.0332

GnomAD4 genome AF: 0.0246 AC: 3740 AN: 152182 Hom.: 57 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74418

Gnomad4 AFR AF: 0.00773

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0795

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.0377

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0375 Hom.: 69

Bravo AF: 0.0261

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:27

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	-	- -

Ataxia-telangiectasia syndrome Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Oct 05, 2015	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:6

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2012	This alteration is classified as benign based on a combination of the following: 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	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 19, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 20, 2024	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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.8786+8A>C variant was identified in 12 of 206 proband chromosomes (frequency: 0.06) from individuals or families with acute lymphoblastic leukemia and was present in 3 of 198 control chromosomes (frequency: 0.02) from healthy individuals (Meier 2005). The variant was also identified in dbSNP (ID: rs4986839) as "With Likely benign, other allele", ClinVar (classified as benign by seven submitters and as likely benign by four submitters) and LOVD 3.0 (4x as benign or likely benign). The variant was identified in control databases in 7055 of 277176 chromosomes (163 homozygous) at a frequency of 0.03, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 165 of 24026 chromosomes (freq: 0.007), Other in 208 of 6464 chromosomes (freq: 0.03), Latino in 582 of 34416 chromosomes (freq: 0.02), European in 4586 of 126678 chromosomes (freq: 0.04), Ashkenazi Jewish in 836 of 10150 chromosomes (freq: 0.08), Finnish in 216 of 25792 chromosomes (freq: 0.008), and South Asian in 462 of 30782 chromosomes (freq: 0.02), while the variant was not observed in the East Asian population. 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 this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely 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
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.16		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: rs4986839; hg19: chr11-108224615; COSMIC: COSV53725850;