chr11-108256249-G-A

Position:

chr11-108256249-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000051.4(ATM):c.2159G>A(p.Arg720His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,609,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R720S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11B:2

Conservation

PhyloP100: 2.92

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13778067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.2159G>A	p.Arg720His	missense_variant	14/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2159G>A	p.Arg720His	missense_variant	14/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251040

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000515

AC:

AN:

1457378

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

725044

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000633

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000397

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 720 of the ATM protein (p.Arg720His). This variant is present in population databases (rs55830714, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer, melanoma, ovarian cancer, and/or urothelial cancer (PMID: 20305132, 28779002, 30287823, 32068069, 33588785, 34262154). ClinVar contains an entry for this variant (Variation ID: 181924). 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 tolerated. 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	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 24, 2020	- -

not provided

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast and prostate cancer but also seen in controls (Decker et al., 2017; Momozawa et al., 2018; Momozawa et al., 2019; Dalmasso et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 19781682, 25428177, 27284491, 28415633, 22529920, 28779002, 25925381, 30287823, 33471991, 29338689, 34262154, 33588785, 32566746, 31214711, 20305132, 32068069) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2022	Variant summary: ATM c.2159G>A (p.Arg720His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 298502 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. c.2159G>A has been reported in the literature in individuals affected with Breast Cancer/or Ovarian cancer (examples: Bernstein_2010, Momozawa_2018, Kwong_2020, Dalmasso_2021 and Dorling_2021) but also in unaffected controls (examples: Momozawa_2018,and Dorling_2021). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. 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	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	This missense variant replaces arginine with histidine at codon 720 of the ATM protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132) including three case-control studies (PMID: 28743247, 30287823, 33471991). In the first case-control study, conducted in the UK, this variant was reported in 1/13087 breast cancer cases and 0/5488 controls (PMID: 28743247). In a second case-control study with Japanese participants, this variant was reported in 10/7051 female breast cancer cases, 28/11241 female controls (OR=0.569, 95%CI 0.2 to 1.2), 0/53 male breast cancer cases, and 19/12490 male controls (PMID: 30287823). A third case-control study included participants from multiple countries and reported this variant in 9/60457 breast cancer cases and 8/53453 controls (OR=0.995, 95%CI 0.384 to 2.578, p-value=1; PMID: 33471991). This variant has been identified in 15/282402 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	Oct 21, 2022	The p.R720H variant (also known as c.2159G>A), located in coding exon 13 of the ATM gene, results from a G to A substitution at nucleotide position 2159. The arginine at codon 720 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in 1/4,112 breast cancer patients and 0/2,399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was observed in with an allele frequency of 0.00142 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00249 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0015 in 12,490 male controls of Japanese ancestry(Momozawa Y et al, 2018 10;9:4083). This alteration has also been reported with a carrier frequency of 0.00196 in 7,636 unselected prostate cancer patients and 0.0015 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This alteration has also been reported in at least one subject in a study of 13,087 breast cancer cases and 5,488 control individuals in the UK (Decker B et al, 2017 11;54:732-741). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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 01, 2019

- -

ATM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2023

The ATM c.2159G>A variant is predicted to result in the amino acid substitution p.Arg720His. This variant has been reported in individuals with breast and/or ovarian cancer (Table S2, Berstein et al. 2010. PubMed: 20305132; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S1, Kwong et al. 2020. PubMed ID: 32068069). It has been reported in a urothelial carcinoma specimen (Additional Data 3, Yang et al. 2021. PubMed ID: 33588785) and a melanoma cohort study (Supplement, Dalmasso et al. 2021. PubMed ID: 34262154). It has also been reported in cases and controls from a breast cancer cohort study and a prostate cancer cohort study (Supplement, Momozawa et al. 2018. PubMed ID: 30287823; Supplement, Momozawa et al. 2020. PubMed ID: 31214711). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108126976-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/181924/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

.;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.76

T;T;.

M_CAP

Benign

0.064

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

.;N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.91

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.090

T;T;T

Sift4G

Benign

0.064

T;D;D

Polyphen

0.52

.;P;P

Vest4

0.14, 0.17

MutPred

0.46

Gain of catalytic residue at L722 (P = 0.0555);Gain of catalytic residue at L722 (P = 0.0555);Gain of catalytic residue at L722 (P = 0.0555);

MVP

0.78

MPC

0.24

ClinPred

0.047

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.16

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