chr11-108293425-G-A

Position:

chr11-108293425-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_000051.4(ATM):c.4724G>A(p.Arg1575His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,612,438 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 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:2

Conservation

PhyloP100: 8.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

BP6

Variant 11-108293425-G-A is Benign according to our data. Variant chr11-108293425-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181960.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4724G>A	p.Arg1575His	missense_variant	31/63	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.4724G>A	p.Arg1575His	missense_variant	31/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250980

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000938

AC:

137

AN:

1460430

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000461

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ATM-related and other cancers, but also in unaffected controls (PMID: 18573109, 19781682, 21933854, 23585524, 26580448, 28779002, 27978560, 29522266, 30287823, 34326862, 36200007); Published functional studies demonstrate no damaging effect: kinase activity similar to wild type (PMID: 18573109, 19431188); This variant is associated with the following publications: (PMID: 18573109, 26580448, 19781682, 23585524, 26787654, 21933854, 26689913, 27720647, 29522266, 19431188, 30287823, 27978560, 33922147, 36029002, 30613976, 28779002, 34326862, 36200007, 36243179) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Athena Diagnostics	Jan 16, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease. (PMID: 19431188) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 09, 2024	BS3 -

Ataxia-telangiectasia syndrome

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This missense variant replaces arginine with histidine at codon 1575 of the ATM protein. Computational prediction suggests that this variant may not affect protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant does not affect kinase activity of ATM protein (PMID: 18573109, 19431188). This variant has been reported in individuals affected with breast cancer, chronic lymphocytic leukemia, and rectal cancer (PMID: 19781682, 23585524, 27978560, 30287823, 36200007), and in unaffected individuals (PMID: 21933854, 30287823, 34262154). This variant has been detected in a breast cancer case-control meta-analysis in 8/60458 breast cancer cases and 6/53455 controls (OR=1.179, 95%CI 0.409 to 3.398, p-value=0.796; PMID: 33471991). This variant has been identified in 16/282324 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	Mar 30, 2023	The p.R1575H variant (also known as c.4724G>A), located in coding exon 30 of the ATM gene, results from a G to A substitution at nucleotide position 4724. The arginine at codon 1575 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in individuals diagnosed with breast cancer and control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Rizzolo P et al. Int J Cancer, 2019 07;145:390-400; Mittal A et al. Ecancermedicalscience, 2022 Aug;16:1434). This alteration has also been identified in individuals diagnosed with CLL, medulloblastoma and early onset colorectal cancer (Skowronska A et al. Haematologica 2012 Jan;97:142-6; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Pearlman R et al. JAMA Oncol. 2017 Apr;3(4):464-471). Functional analysis of this alteration found normal protein levels and kinase activity compared to wild type (Austen B et al. Br. J. Haematol. 2008 Sep;142(6):925-33; Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This amino acid position is highly 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:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Jun 27, 2019	The c.4724G>A variant has been reported in the literature to co-occur with the ATM c.6820G>A variant in individuals with breast cancer, chronic lymphocytic leukemia (CLL) and multiple myeloma (Austen 2008, Tavtigian 2008, and Navrkalova 2012). The individual with CLL also had a somatic ATM Gln984Glu and a somatic 11q chromosomal deletion. The c.4724G>A variant has a combined allele frequency of 0.00006 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant is in an evolutionarily conserved residue. Thus, it is unknown whether this variant increases cancer risk. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 20, 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]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 16, 2023

Variant summary: ATM c.4724G>A (p.Arg1575His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-05 in 255778 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (5.9e-05 vs 0.001), allowing no conclusion about variant significance. c.4724G>A has been reported in the literature in individuals affected with Breast Cancer (e.g. Tavtigian_2009, Momozawa_2018, Rizzolo_2019, Bhai_2021), and in individuals with a variety of other cancers (e.g. Austen_2008, Navrkalova_2012, Pearlman_2016, Lu_2015), but also in healthy controls (e.g. Momozawa_2018, Dalmasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on ATM kinase activity (Austen_2008). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Seven submitters classified the variant as uncertain significance and one classified it as likely benign. The following publications have been ascertained in the context of this evaluation (PMID: 18573109, 34262154, 26689913, 30287823, 23585524, 27978560, 19781682, 26787654, 30613976, 34326862). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Sep 09, 2024

According to the ClinGen ACMG ATM v1.3.0 criteria we chose this criterion: BS3 (supporting benign): Barone 2009 (& Austen et al. (2008), PMID: 18573109): stable ATP kinase activity (s. Supp. Figure S1) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

-0.057

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.70

MutPred

0.47

Loss of MoRF binding (P = 0.0176);Loss of MoRF binding (P = 0.0176);

MVP

0.94

MPC

0.62

ClinPred

0.78

GERP RS

4.4

Varity_R

0.42

gMVP

0.59

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