rs587781894

chr11-108365360-G-Achr11-108365360-G-Cchr11-108365360-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000051.4(ATM):c.9023G>A(p.Arg3008His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,000 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3008G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.52

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 Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 16) in uniprot entity ATM_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000051.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-108365359-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 142187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

PP5

Variant 11-108365360-G-A is Pathogenic according to our data. Variant chr11-108365360-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108365360-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.9023G>A	p.Arg3008His	missense_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.9023G>A	p.Arg3008His	missense_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251410

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135886

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:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727232

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:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 02, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 29, 2023	The p.R3008H variant (also known as c.9023G>A), located in coding exon 62 of the ATM gene, results from a G to A substitution at nucleotide position 9023. The arginine at codon 3008 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was reported in conjunction with a nonsense ATM mutation in a child with ataxia-telangiectasia (A-T). In the same study, this alteration was detected in 1/122 breast cancer patients with a family history of both breast cancer and a hematological malignancy and was not seen in any of the 186 control patients (Paglia LL et al. Breast Cancer Res.Treat. 2010; 119:443-52). This variant has also been reported in conjunction with a frameshift ATM mutation in a Norwegian patient with A-T (Strand J et al. Front Immunol, 2020 Jul;11:1417). This variant was also reported in conjunction with a leaky splice site variant in ATM in a 45 year old patient and in three siblings with variant type A-T (Schon K et al. Ann. Neurol., 2019 02;85:170-180; Caputi C et al. Mov Disord Clin Pract, 2023 Jan;10:124-129). A functional study performed in p.R3008H expressing mice demonstrated the mice are viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared to Atm-/- controls; the mutant animals also displayed cell cycle checkpoint defects and reduced lymphocyte development (Milanovic M et al. Cancer Res, 2021 Jan;81:426-437). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	The c.9023G>A (p.Arg3008His) variant has an allele frequency of 0.00075%, (2/268,268 alleles) in the gnomAD v2.1.1 non-cancer dataset, since it has been found once in the Finnish subpopulation (1/25,106) and once in the European non-Finnish subpopulation (1/118,102 alleles) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive. On the other side, it is located at the somatic mutational hotspot codon p.Arg3008 (PM1). Moreover, the pathogenic variant c.9022C>T p.(Arg3008Cys) is located in the same codon. This variant was detected in two ataxia-telangiectasia probands (PS4_Moderate; PMID: 30549301, 21665257). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM1 + PS4_Moderate (PMID: 33280026). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 21, 2023	This missense variant replaces arginine with histidine at codon 3008 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Mouse models carrying this variant were immunodeficient and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with wild type controls (PMID: 33239428). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 21665257, 30549301). This variant has also been reported in individuals with a personal and/or family history of breast cancer or colorectal cancer (PMID: 19404735, 29752822, 31118792). In addition, a different variant affecting the same amino acid position (p.Arg3008Cys) is considered to be disease-causing (ClinVar variation ID: 142187), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 2/246168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Ataxia-telangiectasia syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3008 of the ATM protein (p.Arg3008His). This variant is present in population databases (rs587781894, gnomAD 0.004%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or personal or family history of breast, ovarian, and/or colon cancer (PMID: 2166257, 19404735, 21665257, 29752822, 31118792, 32754152). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141634). 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. This variant disrupts the p.Arg3008 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9872980, 10817650, 12552566, 15101044, 18573109, 19431188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 32754152]. Functional studies indicate this variant impacts protein function [PMID: 33239428, 12552566, 18573109, 23585524]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2023	- -

Gastric cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 04, 2023

Observed in a patient with ataxia telangiectasia who harbored an ATM truncating variant, but information regarding phase (variants in cis or trans) was not provided (PMID: 21665257); Observed in the heterozygous state in individuals with a personal or family history of breast, colorectal, and other cancers (PMID: 19404735, 31118792, 29752822, 33436325); Published functional studies demonstrate a damaging effect: reduced or normal ATM protein expression, deficient p21 induction, and reduced ATM kinase activity (PMID: 11756177, 33239428, 23585524); 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); This variant is associated with the following publications: (PMID: 17968022, 12697903, 25742471, 12149228, 28152038, 27586204, 29752822, 30620386, 19404735, 22529920, 10397742, 11756177, 23585524, 21933854, 27714650, 23103869, 26536348, 25925381, 26205736, 29316426, 29922827, 29946849, 29866652, 27194209, 28652578, 30549301, 30855176, 31118792, 32754152, 33332384, 33436325, 32873698, 34771661, 33598286, 33280026, 35480123, 33239428, 34556870, 34151669, 35347810, 31263571, 33536256, Villaruz2022[Abstract], 23532176, 21665257, 35264596, 35886069) -

Malignant tumor of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 11, 2022

Variant summary: ATM c.9023G>A (p.Arg3008His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of 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 8e-06 in 251410 control chromosomes (gnomAD). c.9023G>A has been reported in the literature in individuals affected with Breast Cancer (Li_2018, Pagila_2010), Ataxia-Telangiectasia (Micol_2011, Schon_2019), colorectal cancer (Gong_2019), along with multiple somatic occurrences (Austen_2007, Camacho_2002, Chang_2015, Fang_2003, Gronbaek_2002, Ida_2019, Navrkalova_2013, Schaffner_1999). These data indicate that the variant is likely to be associated with disease. In addition, another missense change at this position, R3008C, has been highly reported to be associated with cancer and A-T. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic (n=7)/pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.0

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.71

MutPred

0.54

Loss of MoRF binding (P = 0.0046);Loss of MoRF binding (P = 0.0046);

MVP

0.97

MPC

0.63

ClinPred

0.98

GERP RS

5.2

Varity_R

0.48

gMVP

0.78

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