11-108330287-C-T

Position:

chr11-108330287-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000051.4(ATM):c.7381C>T(p.Arg2461Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000613 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:4O:1

Conservation

PhyloP100: 4.54

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 11-108330287-C-T is Benign according to our data. Variant chr11-108330287-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142541.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, not_provided=1, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7381C>T	p.Arg2461Cys	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.7381C>T	p.Arg2461Cys	missense_variant	50/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251274

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000158

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27498913, 27443514, 26010451, 27978560, 29356034, 29058119, 27304073, 24983367, 33280026, 32832836, 31617914, Carpenter2024[computational], 23532176) -
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	Mar 01, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This missense variant replaces arginine with cysteine at codon 2461 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and 3/53461 controls (OR=1.768, 95%CI 0.442 to 7.071, p-value=0.515; PMID: 33471991). This variant has also been reported in individuals affected with early-onset or bilateral breast cancer (Color internal data), early-onset prostate cancer (PMID: 29356034), colorectal cancer (PMID: 28135145, 27978560), sarcoma (PMID: 27498913), and endometrial carcinoma (PMID: 27443514). This variant has been identified in 26/282686 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 16, 2023	The p.R2461C variant (also known as c.7381C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7381. The arginine at codon 2461 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in two individuals who underwent multi-gene panel testing and was classified as a variant of unknown significance. One individual was diagnosed with endometrial cancer and the other with early-onset colorectal cancer (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-9; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration was also reported in the heterozygous state in a Caucasian male meeting Chompret criteria who was diagnosed with spindle cell sarcoma of the liver at age 42 years (Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71). In addition, this alteration was also observed in individuals diagnosed with prostate cancer (Beebe-Dimmer JL et al. Prostate, 2018 04;78:321-326; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.7381C>T (p.Arg2461Cys) variant has an allele frequency of 0.000093 (0.009%, 25/268,148 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00064 (0.06%, 15/23,620 alleles) in the Afican subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration as per SPiCE predictor. A cryptic acceptor site is activated according to SpliceSiteFinderlike and MaxEnt, but its score slightly exceeds the natural one only according to SpliceSiteFinderlike and no splicing site is created/activated according to NNSplice and GeneSplicer. However, missense variant alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 (PMID: 33280026). -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 07, 2024	- -

Ataxia-telangiectasia syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 21, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial cancer of breast

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 13, 2024	This variant is considered likely 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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ATM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 25, 2022

The ATM c.7381C>T variant is predicted to result in the amino acid substitution p.Arg2461Cys. This variant has been reported in individuals with endometrial, colorectal, and prostate cancer (Ring et al. 2016. PubMed ID: 27443514, Table S2; Pearlman et al. 2017. PubMed ID: 27978560, eTable 2; Beebe-Dimmer et al. 2018. PubMed ID: 29356034). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108201014-C-T) and is interpreted as uncertain significance by the vast majority of clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142541/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 30, 2023

Variant summary: ATM c.7381C>T (p.Arg2461Cys) results in a non-conservative amino acid change in 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 8.4e-05 in 251274 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.4e-05 vs 0.004), allowing no conclusion about variant significance. c.7381C>T has been reported as a VUS in the literature in individuals undergoing hereditary cancer panel testing for a variety of cancer indications (example, Ring_2016, Pearlman_2017, Feliubadalo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/breast cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.2744_2745delCT, p.Ser915*), providing supporting evidence for a benign role in relationship to breast cancer but not Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=7; likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely benign and reported on 01-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;D

Vest4

0.72

MVP

0.97

MPC

0.54

ClinPred

0.33

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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