11-108267276-T-C

Variant names:

• chr11-108267276-T-C
• rs1800056
• NM_000051.4:c.2572T>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.2572T>C​(p.Phe858Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,614,054 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:30 O:1
• Conservation: PhyloP100: 2.94

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 (MetaRNN=0.0052860677).
• BP6: Variant 11-108267276-T-C is Benign according to our data. Variant chr11-108267276-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 132736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108267276-T-C is described in Lovd as [Benign]. Variant chr11-108267276-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00836 (1273/152228) while in subpopulation NFE AF= 0.0141 (962/68002). AF 95% confidence interval is 0.0134. There are 7 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2572T>C	p.Phe858Leu	missense_variant	Exon 17 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2572T>C	p.Phe858Leu	missense_variant	Exon 17 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1274 AN: 152110 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00865 AC: 2175 AN: 251440 Hom.: 21 AF XY: 0.00878 AC XY: 1193 AN XY: 135892

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.0115 AC: 16837 AN: 1461826 Hom.: 126 Cov.: 31 AF XY: 0.0113 AC XY: 8222 AN XY: 727224

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00512

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00457

Gnomad4 NFE exome AF: 0.0137

Gnomad4 OTH exome AF: 0.00950

GnomAD4 genome AF: 0.00836 AC: 1273 AN: 152228 Hom.: 7 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74434

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0132 Hom.: 43

Bravo AF: 0.00832

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00914 AC: 1110

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0128

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Sep 11, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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:7

May 04, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

Mar 31, 2017

Counsyl

Significance: Likely 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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

May 23, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 13, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 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. -

Nov 21, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: BS1, BS2 -

Apr 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATM c.2572T>C variant affects a conserved nucleotide, resulting in an amino acid change from Phe to Leu. 4/4 in-silico tools predict benign outcome for this variant (SNPs&GO not captured due to low reliability index), and a functional test based on p21 gene induction after parallel treatment of leukemic cells with fludarabine and doxorubicinfunctional support a benign outcome (Navrkalova_Haematologica_2013). This variant was found in 1165/126138 control chromosomes (16 homozygotes) at a frequency of 0.0092359, which is about 2 times of the maximal expected frequency of an ATM pathogenic allele (0.0039528), suggesting this variant is benign. The variant was included in several risk association studies, 5/6 of which found no significanct association between the variant and breast cancer, however one association study found a statistically significant association with the F858L polymorphism and chronic lymphocytic leukemia risk, both alone and in combination with the second ATM polymorphism P1054R, which are in strong linkage disequilibrium (Rudd_2006). In addition, clinical laboratories classified this variant as benign. Taken together, this variant was classified as benign. -

Oct 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Phe858Leu variant was identified in 190 of 15454 proband chromosomes (frequency: 0.01) from individuals or families with breast, colon cancer and chronic lymphocytic leukemia, and was present in 672 of 18488 control chromosomes (frequency: 0.036) from healthy individuals (Johnson 2007, Petereit 2013, Renwick 2006, Rudd 2017, Stredrick 2006, Tapia 2008, Webb 2006). The variant was also identified in the following databases dbSNP (ID: rs1800056) as “With Uncertain significance allele ”, ClinVar (classified as benign by GeneDx, Ambry Genetics, Emory Genetics, Vantari Genetics, Color Genomics, Prevention Genetics, Invitae; classified as uncertain significance by Praxis), Clinvitae (classified as benign by ClinVar), Cosmic, MutDB (classified as polymorphism), LOVD 3.0 (not classified), ATM-LOVD (unknown). ATM-LOVD also reports that there are known homozygous individuals who are unaffected. The variant was identified in control databases in 2373 of 277178 chromosomes (22 homozygous) at a frequency of 0.009 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 1805 of 126686 chromosomes (freq: 0.014), Ashkenazi Jewish in 135 of 10150 chromosomes (freq: 0.013), Other in 70 of 6466 chromosomes (freq: 0.011). The p.Phe858 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 of impact to 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. There is conflicting information in the literature about the association of the p.Phe858Leu variant with an increased risk of cancer. The study by Fletcher (2010) suggests the variant associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. The study by Stredrick (2006) suggests the variant is associated with a significant increased risk for breast cancer in the U.S. Heterozygote frequencies for p.Phe858Leu were slightly higher in subjects with a first degree relative with breast cancer compared to those with a negative family history. The variant was found in strong linkage disequilibrium associated with increased risk of chronic lymphocytic leukemia (Rudd 2017). Cell lines from breast cancer patients harboring the linked heterozygous p.Phe858Leu variants exhibited increased radiosensitivity (Gutiérrez-Enríquez 2004). The variant is also showing a significant association with risk of colon cancer and predicted to be deleterious by Webb (2006). The minor alleles of ATM p.Phe858Leu were significantly over-represented in cases, compared with controls. At the same time Tapia (2008) suggests this variant is not associated with breast cancer in his group of study showing higher frequencies in the control group than in cases. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Breast and/or ovarian cancer Benign:1

May 24, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait Benign:1

May 31, 2021

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We examined a family. The child is toe-walker and has Phe858Leu variant. Father is not toe-walker and he has this variant too. This variant probably has no clinical relevance, as it occurs frequently, and no disease relevance is predicted for the amino acid change from phenylalanine to leucine according to the calculation of various in-silico prediction programs (Polyphen2, SIFT, Mutation Taster). In the ClinVar mutation database there are also mostly entries "benign" and "likely benign" vs.VUS. Gait disorder -

Familial cancer of breast Benign:1

May 09, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.59	T;T;.
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.035	D;T;T
Sift4G	Uncertain	0.032	D;T;T
Polyphen		0.73	.;P;P
Vest4		0.24, 0.26
MutPred		0.083		Loss of stability (P = 0.0937);Loss of stability (P = 0.0937);Loss of stability (P = 0.0937);
MVP		0.98
MPC		0.15
ClinPred		0.042	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.33

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: rs1800056; hg19: chr11-108138003; COSMIC: COSV53728338; COSMIC: COSV53728338;