rs3092829

Positions:

• chr11-108304667-T-C

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.5497-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,612,812 control chromosomes in the GnomAD database, including 710 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 0.021 (36 hom., cov: 32)
  • Exomes 𝑓: 0.028 (674 hom.)
• Consequence: ATM NM_000051.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006728
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.28

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=-0.81).
• BP6: Variant 11-108304667-T-C is Benign according to our data. Variant chr11-108304667-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 132706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108304667-T-C is described in Lovd as [Benign]. Variant chr11-108304667-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0215 (3271/152312) while in subpopulation NFE AF= 0.0329 (2238/68020). AF 95% confidence interval is 0.0318. There are 36 homozygotes in gnomad4. There are 1549 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5497-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5497-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3272 AN: 152194 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00526

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0329

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0225 AC: 5630 AN: 250650 Hom.: 89 AF XY: 0.0226 AC XY: 3059 AN XY: 135528

Gnomad AFR exome AF: 0.00567

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00615

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0283 AC: 41334 AN: 1460500 Hom.: 674 Cov.: 31 AF XY: 0.0280 AC XY: 20345 AN XY: 726626

Gnomad4 AFR exome AF: 0.00490

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00624

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0324

Gnomad4 OTH exome AF: 0.0261

GnomAD4 genome AF: 0.0215 AC: 3271 AN: 152312 Hom.: 36 Cov.: 32 AF XY: 0.0208 AC XY: 1549 AN XY: 74486

Gnomad4 AFR AF: 0.00524

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.0329

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0299 Hom.: 59

Bravo AF: 0.0214

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0329

EpiControl AF: 0.0321

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

Ataxia-telangiectasia syndrome Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 22, 2015	- -
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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 08, 2018	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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 02, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 29, 2013	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 23, 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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Triple-negative breast carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The ATM c.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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. -

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.5497-8T>C variant was identified in 37 of 1416 proband chromosomes (frequency: 0.026) from individuals or families with breast cancer (Concannon 2008, Paglia 2010). The variant was also identified in dbSNP (ID: rs3092829) as “With Benign allele”, ClinVar (5x, as benign by Invitae, Ambry Genetics, Vantari, PreventionGenetics, Color Genomics), Clinvitae (3x, as benign), Cosmic (4x, in ovary carcinoma, and soft tissue Haemangioblastoma), LOVD 3.0 (1x with "does not affect function"), databases. The variant was not identified in GeneInsight-COGR, MutDB and ATM-LOVD, databases. The variant was identified in control databases in 6238 (94 homozygous) of 276468 chromosomes at a frequency of 0.0225 increasing the likelihood this could be a benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) in 4209 (69 homozygous) of 126224 chromosomes (freq: 0.033), other in 181 (3 homozygous) of 6446 chromosomes (freq: 0.028), European (Finnish) in 650 (10 homozygous) of 25722 chromosomes (freq: 0.025), Ashkenazi Jewish* in 236 (4 homozygous) of 10138 chromosomes (freq: 0.023), Latino in 631 (7 homozygous) of 34354 chromosomes (freq: 0.018). The c.5497-8T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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. -

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.4
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.0040
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: rs3092829; hg19: chr11-108175394; COSMIC: COSV53727999; COSMIC: COSV53727999;