11-108330381-T-G

Position:

chr11-108330381-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000051.4(ATM):c.7475T>G(p.Leu2492Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:22B:2

Conservation

PhyloP100: 7.51

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]

ATM links:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7475T>G	p.Leu2492Arg	missense_variant	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7475T>G	p.Leu2492Arg	missense_variant	50/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251282

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000177

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000237

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:22Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colon, and other cancers (PMID: 17344846, 26689913, 28779002, 28652578, 28135145, 30306255, 29522266, 30441849, 29684080, 32606146, 35347810, 35886069, 35127508, 36029002); Present at similar frequency among breast cancer cases and controls in a large case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 35347810, 35127508, 35886069, 22529920, 17344846, 26689913, 25980754, 26787654, 22173549, 28873162, 28135145, 28652578, 26206375, 29522266, 28779002, 29684080, 30306255, 31159747, 31422574, 20305132, 30441849, 31920950, 32606146, 35047863, 36011273, 34284872, 23532176, 34718612, 33471991, 34262154, 35980532, 36029002, 37351993) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATM: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 14, 2021	In the published literature, this variant has been reported in a control individual and in individuals affected with breast cancer (PMID: 30306255 (2018), 28779002 (2017), 20305132 (2010)), ovarian cancer (PMID: 30441849 (2018)), lung adenocarcinoma (PMID: 17344846 (2007)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), glioblastoma (PMID: 26689913 (2015)), prostate cancer (PMID: 32606146 (2020)), and Lynch syndrome-associated cancer and/or polyps (PMID: 28135145 (2017), 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00039 (13/33062 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Ataxia-telangiectasia syndrome

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2019	The ATM c.7475T>G; p.Leu2492Arg variant (rs56399857) is reported in the literature in individuals with colorectal cancer (Yurgelun 2017), chronic lymphocytic leukemia (Tiao 2017), and glioblastoma multiforme (Lu 2015). This variant is reported with uncertain significance by multiple laboratories in ClinVar (Variation ID: 127446). It is found in the general population with an overall allele frequency of 0.01% (32/282684 alleles) in the Genome Aggregation Database. The leucine at codon 2492 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Tiao G et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017 Oct;31(10):2244-2247. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 2024	The p.L2492R variant (also known as c.7475T>G), located in coding exon 49 of the ATM gene, results from a T to G substitution at nucleotide position 7475. The leucine at codon 2492 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in multiple cohorts of individuals referred for genetic testing (Lu C et al. Nat Commun. 2015 Dec;6:10086; Tiao G et al. Leukemia. 2017 10;31:2244-2247; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast

Pathogenic:1Uncertain:2

Likely pathogenic, flagged submission	clinical testing	Clinical Cancer Genetics and Family Consultants, Athens Medical Center	Jun 27, 2019	This variant is denoted ATM c.7475T>G at the cDNA level, p.Leu2492Arg at the protein level, and is a non-conservative amino acid change located in the PIK-related kinase, FAT domain (Stracker 2013) of the encoded protein sequence. Five of five in silico tools predict a damaging effect of this variant on protein function. This is a rare variant (ExAC 0.00006), and has been reported in various cancers (Lu 2015, Greenman 2007, Berstein 2010). We report this variant to occur in two sisters, both heterozygotes, with breast cancer, of 47 and 50 years old. The second one also developed thyroid cancer at the age of 55. A third sister tested, is a healthy non-carrier at the age of 59 years old. The family on the paternal side included one case of breast cancer at the age of 70 years old, and another one with breast and thyroid cancer at the age of 40 and 65 years old respectively. For these reasons, this variant may be causative of disease in this family and we classify it as probably pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 27, 2022	The ATM c.7475T>G (p.Leu2492Arg) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with many cancer types including breast, colorectal, prostate, pancreatic, and chronic lymphocytic leukemia (PMID: 28135145, 28652578, 30306255, 32606146, 35047863). This variant has been reported in 5 individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2021	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.7475T>G, in exon 50 that results in an amino acid change, p.Leu2492Arg. This sequence change has been described in the gnomAD database with a frequency of 0.024% in the European (Non-Finnish) subpopulation (dbSNP rs56399857). The p.Leu2492Arg change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Leu2492Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously identified in individuals who have undergone hereditary cancer genetic testing (PMID: 31159747, 25980754) and in an individual with a history of unilateral breast cancer (PMID: 20305132) and in an individual with a history colon cancer (28135145). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Leu2492Arg change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2024	Variant summary: ATM c.7475T>G (p.Leu2492Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251282 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (9.9e-05 vs 0.001), allowing no conclusion about variant significance. c.7475T>G has been reported in the literature primarily as a VUS in settings of multigene panel testing in individuals affected with breast, prostate, and other cancers and also in healthy controls (e.g. Bernstein_2010, Greenman_2007, Lu_2015, Tiao_2017, Young_2016, Yurgelun_2015, Yurgelun_2017, Bonache_2018, Tsaousis_2019, Holeckova_2020, Krivokuca_2022, Paduano_2022). In addition, the variant was found in 5/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 30306255, 17344846, 32606146, 34284872, 26689913, 35886069, 28652578, 31159747, 26787654, 25980754, 28135145). ClinVar contains an entry for this variant (Variation ID: 127446). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2024

The ATM c.7475T>G variant is predicted to result in the amino acid substitution p.Leu2492Arg. This variant has been reported in individuals with breast cancer, ovarian cancer, chronic lymphocytic leukemia, colorectal cancer, lynch syndrome, and glioblastoma multiforme (Table S1, Bernstein et al. 2010. PubMed ID: 20305132; Table S2, Yurgelun et al. 2015. PubMed ID: 25980754; Table S12, Lu et al. 2015. PubMed ID: 26689913Table S5, Decker et al. Decker et al. 2017. PubMed ID: 28779002; Table S3, Tiao et al. 2017. PubMed ID: 28652578; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table 2, Bonache et al. 2018. PubMed ID: 30306255; Table S1, Koczkowska et al. 2018. PubMed ID: 30441849; Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/127446/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Astroblastoma, MN1-altered

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

0.99

MPC

0.70

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.86

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over