rs55982963

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000051.4(ATM):c.8156G>A(p.Arg2719His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,612,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2719C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:23B:1

Conservation

PhyloP100: 3.27

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 1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000051.4

BP4

Computational evidence support a benign effect (MetaRNN=0.30260932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.8156G>A	p.Arg2719His	missense_variant	56/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.8156G>A	p.Arg2719His	missense_variant	56/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000148

AC:

AN:

250828

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1460268

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000559

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:23Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:8

Uncertain significance, 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 27, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2719 of the ATM protein (p.Arg2719His). This variant is present in population databases (rs55982963, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer (PMID: 18384426, 19781682, 21445571, 35264596). ClinVar contains an entry for this variant (Variation ID: 127456). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2021	- -

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 27, 2020	- -
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	GeneDx	Jun 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast or other cancers, but also in unaffected controls (Brunet et al., 2008; Balbs-Martnez et al., 2013; Tung et al., 2015; Maxwell et al., 2016; Mucaki et al., 2016; Decker et al., 2017; Velazquez et al., 2020; Dorling et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 21445571, 25503501, 18384426, 22529920, 19781682, 24121791, 26580448, 25525159, 27153395, 27067391, 25925381, 30197789, 17344846, 25186627, 28652578, 30287823, 34426522, 35312250, 23532176, 15279808, 36029002, 33471991, 32522261, 35264596, 28779002) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	May 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2017	Variant summary: The c.8156G>A (p.Arg2719His) in ATM gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is located in the PI3/PI4-kinase domain, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.00017 (20/116502 chrs tested), predominantly in individuals of Latino descent (0.0017; 13/1130chrs tested), including 1 homozygote. The latter frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.0010, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pts without strong evidence for causality. The variant is cited as VUS by a reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2024	This missense variant replaces arginine with histidine at codon 2719 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. The variant has been reported in individuals affected with breast cancer (PMID: 18384426, 19781682, 35312250, 33471991, 35312250), as well as in two women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). In a large international case-control meta-analysis, this variant was reported in 22/60466 cases breast cancer cases and 11/53461 controls (OR=1.769, 95%CI 0.858 to 3.648, p-value=0.162; PMID: 33471991). This variant has also been identified in 37/250828 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including 1 homozygous individual. 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	curation	Sema4, Sema4	Nov 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 25, 2022	The p.R2719H variant (also known as c.8156G>A), located in coding exon 55 of the ATM gene, results from a G to A substitution at nucleotide position 8156. The arginine at codon 2719 is replaced by histidine, an amino acid with highly similar properties. This alteration was first reported in Spanish early-onset breast cancer patients who had tested negative for mutations in the BRCA1 and BRCA2 genes (Brunet J et al. Clin. Genet. 2008 May;73:465-73). and in a Peruvian female with high-grade cribriform ductal carcinoma in situ (Sánchez Castro EE et al. Rev Fac Cien. Med Univ Nac Cordoba. 2022 03;79(1):53-56.). Across numerous studies, the p.R2719H alteration was observed in 1/4112 breast cancer cases and 0/2399 control individuals (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). 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. -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Oct 08, 2019	This variant has been reported in the literature in individuals with breast cancer (Brunet 2008, Tavtigian 2009, Grana 2011). This variant has an overall allele frequency of 0.0001 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3 -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 18, 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	MGZ Medical Genetics Center	Sep 02, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2021	- -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 22, 2022

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.46

N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.60

MVP

0.94

MPC

0.63

ClinPred

0.27

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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