11-108304667-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000051.4(ATM):​c.5497-8T>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 0.0277 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, intron

Scores

2
Splicing: ADA: 0.00006728
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26

Conservation

PhyloP100: 1.28
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
ATMNM_000051.4 linkc.5497-8T>C splice_region_variant, intron_variant Intron 36 of 62 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.5497-8T>C splice_region_variant, intron_variant Intron 36 of 62 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0215
AC:
3272
AN:
152194
Hom.:
36
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:26
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Benign
Review Status: no assertion criteria provided
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

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
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

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Benign:6
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 22, 2015
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 01, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 08, 2018
Illumina Laboratory Services, Illumina
Significance: 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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:4
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATM: BP4, BS1, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Nov 27, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Apr 02, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 23, 2015
Vantari Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 29, 2013
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: 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. -

Familial cancer of breast Benign:2
May 23, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Triple-negative breast carcinoma 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 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
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3092829; hg19: chr11-108175394; COSMIC: COSV53727999; COSMIC: COSV53727999; API