11-108267276-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F858?) has been classified as Pathogenic.

• 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:28 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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108267276-TTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 1793256.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.2572T>C	p.Phe858Leu	missense_variant	17/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.2572T>C	p.Phe858Leu	missense_variant	17/63		NM_000051.4	P1

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:28 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ataxia-telangiectasia syndrome Benign:7

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	May 04, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 14, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 13, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATM: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2016	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. -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

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

May 24, 2019

- -

Tip-toe gait Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 31, 2021

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. -

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
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Uncertain	0.99
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
MutationTaster	Benign	1.0	N;N
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;