rs4988111

Variant names:

• chr11-108327664-T-C
• rs4988111
• NM_000051.4:c.6995T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108327664-T-C
• chr11-108327664-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP2_Strong BP4 BA1

This summary comes from the ClinGen Evidence Repository: The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157165/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.0060 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (11 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign reviewed by expert panel B:27 O:1
• Conservation: PhyloP100: 3.53

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6995T>C	p.Leu2332Pro	missense_variant	Exon 48 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6995T>C	p.Leu2332Pro	missense_variant	Exon 48 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152158 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00162 AC: 407 AN: 251036 Hom.: 7 AF XY: 0.00116 AC XY: 157 AN XY: 135676

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461632 Hom.: 11 Cov.: 30 AF XY: 0.000528 AC XY: 384 AN XY: 727120

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152276 Hom.: 12 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74466

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.000963 Hom.: 4

Bravo AF: 0.00694

ESP6500AA AF: 0.0248 AC: 109

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:27 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7 Other:1

Oct 21, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Dec 01, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

not provided Benign:6

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BP4, BS1, BS2 -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Mar 21, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 12, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 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. -

Jun 18, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Benign:3

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2022

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Jun 12, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Breast and/or ovarian cancer Benign:1

Nov 13, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Benign:1

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Leu2332Pro variant was identified in 6 of 2720 proband chromosomes (frequency: 0.002) from American and Brazilian individuals or families with Lynch syndrome or sporadic breast cancer and was not identified in 200 chromosomes from healthy individuals (Yurgelun_2015_25980754 , Mangone_2015_25625042). The variant was also identified in dbSNP (ID: rs4988111) “With Likely benign, Uncertain significance allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae; likely benign by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics); and classification not provided by ITMI), Clinvitae (4x); and was not identified in GeneInsight-COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 557 (7 homozygous) of 276772 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 515 (7 homozygous) of 24026 chromosomes (freq: 0.02), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 27 of 34410 chromosomes (freq: 0.0008), European Non-Finnish in 9 of 126350 chromosomes (freq: 0.00007), Ashkenazi Jewish in 1 of 10138 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003) while not observed in the East Asian and European Finnish, populations. The p.Leu2332 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Pro impacts the protein; however, this information is not predictive enough to rule out pathogenicity. 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. -

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	T;.
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.19
Sift	Benign	0.29	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0050	B;B
Vest4		0.19
MVP		0.84
MPC		0.20
ClinPred		0.010	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.55

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: rs4988111; hg19: chr11-108198391; COSMIC: COSV104592081; COSMIC: COSV104592081;