11-108292760-C-T

Variant names:

• chr11-108292760-C-T
• rs1800889
• NM_000051.4:c.4578C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.4578C>T​(p.Pro1526Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 1,613,832 control chromosomes in the GnomAD database, including 1,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (123 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1737 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: -0.292

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-108292760-C-T is Benign according to our data. Variant chr11-108292760-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108292760-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.4578C>T	p.Pro1526Pro	synonymous_variant	Exon 30 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4578C>T	p.Pro1526Pro	synonymous_variant	Exon 30 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4727 AN: 152024 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00918

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0293

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0510

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0326 AC: 8190 AN: 251362 Hom.: 199 AF XY: 0.0323 AC XY: 4393 AN XY: 135846

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.0310

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0356

GnomAD4 exome AF: 0.0452 AC: 66121 AN: 1461690 Hom.: 1737 Cov.: 32 AF XY: 0.0441 AC XY: 32045 AN XY: 727148

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.0307

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.0280

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0384

GnomAD4 genome AF: 0.0311 AC: 4727 AN: 152142 Hom.: 123 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74388

Gnomad4 AFR AF: 0.00916

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.0249

Gnomad4 NFE AF: 0.0511

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0436 Hom.: 297

Bravo AF: 0.0296

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.0486

EpiControl AF: 0.0407

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:10

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Aug 24, 2017

Eurofins Ntd Llc (ga)

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 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

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 Laboratory, Department of Pathology, Netherlands Cancer Institute

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

- -

Ataxia-telangiectasia syndrome Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 26, 2019

Natera, Inc.

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

- -

Hereditary cancer-predisposing syndrome Benign:5

May 22, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 19, 2014

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: 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. -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11505391, 27599564) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cancer of breast Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

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 p.Pro1526= variant was identified in 520 of 9784 proband chromosomes (frequency: 0.05) from individuals or families with unselected multiple myeloma, breast cancer and was identified in 395 of 6700 control chromosomes (frequency: 0.059) from healthy individuals (Austen 2008, Concannon 2008, Petereit 2013, Stredrick 2006, Tommiska 2006). The variant was also identified in dbSNP (ID: rs rs1800889) as “other”, ClinVar (classified as benign by Invitae, Ambry Genetics, Prevention Genetics, Color Genomics; classified as likely benign by Illumina, GSLUOC), Cosmic (classified as neutral), LOVD 3.0 (does not affect function), databases. The variant was not identified in GeneInsight-COGR, MutDB, ATM-LOVD, databases. The variant was identified in control databases in 9064 (227 homozygous) of 277100 chromosomes at a frequency of 0.03 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%: European (Non-Finnish) in 6425 of 126614 chromosomes (freq: 0.051), Other in 212 of 6458 chromosomes (freq: 0.033), Latino in 1062 of 34414 chromosomes (freq: 0.031), European (Finnish) in 641 of 25788 chromosomes (freq: 0.025), Ashkenazi Jewish* in 131 of 10146 chromosomes (freq: 0.013), South Asian in 396 of 30782 chromosomes (freq: 0.013). The p.Pro1526Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, few studies suggest the variant not associated with breast cancer risk and classify the variant as SNP (Stredrick 2006, Tommiska 2006). 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	-0.44
CADD	Benign	6.5
DANN	Benign	0.48

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: rs1800889; hg19: chr11-108163487; COSMIC: COSV53726209; COSMIC: COSV53726209;