11-108365359-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):c.9022C>T(p.Arg3008Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,614,004 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 5.75

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 chr11-108365360-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 11-108365359-C-T is Pathogenic according to our data. 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. Variant chr11-108365359-C-T is described in Lovd as [Pathogenic]. Variant chr11-108365359-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.9022C>T	p.Arg3008Cys	missense_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.9022C>T	p.Arg3008Cys	missense_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

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: 0.0000159 AC: 4 AN: 251428 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135890

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000222 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia as well as cancer (ClinVar, PMIDs: 30549301, 9334731, 22649200; 32918381). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blot in patients' blood did not detect residual activity (PMID: 22649200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3008 of the ATM protein (p.Arg3008Cys). This variant is present in population databases (rs587782292, gnomAD 0.007%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) and/or breast cancer (PMID: 9872980, 10817650, 12552566, 30549301). 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: 142187). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 12552566, 15101044, 18573109). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 13, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12552566 , 15101044 , 18573109). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.86). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 12552566 , 30549301 , 9872980). Different missense changes at the same codon (p.Arg3008His, p.Arg3008Leu, p.Arg3008Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000141634 , VCV000806734 , VCV000822905). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Arg3008Cys variant was identified in 3 of 1508 proband chromosomes (frequency: 0.002) from individuals or families with AtaxiaTelangiectasia and CLL (Navrkalova 2013, Reiman 2011, Skowronska 2012). The variant was also identified in ClinVar (classified as pathogenic by Ambry genetics, GeneDx, Invitae; classified as likely pathogenic by Counsyl), Cosmic (classified as pathogenic), MutDB, and ATM-LOVD databases. The variant was not identified in Genesight-COGR, and LOVD 3.0 databases. The variant was identified in control databases in 4 of 246188 chromosomes at a frequency of 0.000016 in the following populations: African in 1 of 15304 chromosomes (freq. 0.00006), East Asian in 1 of 17244 chromosomes (freq. 0.00006), European (Non-Finnish) in 2 of 111646 chromosomes (freq. 0.00002), but not seen in Ashkenazi Jewish, European (Finnish), Latino, South Asian or other populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017)". The p.Arg3008 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Phosphatidylinositol 3-/4-kinase, catalytic functional domain increasing the likelihood that it may have clinical significance. In addition, several studies reported the expressed R3008C mutant ATM protein showed absence of ATM kinase activity, and strongly suggest that the 9022C>T (R3008C) missense mutation is the disease causing mutation (Angele 2003, Austen 2008,). The Taylor (2005) identified this variant in homozygous state with total absence of ATM kinase activity, although the amount of ATM protein expressed was about half that of normal cells. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant abolishes the protein's kinase activity (PMID: 19431188, 18573109). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2022	Published functional studies demonstrate a damaging effect showing loss of ATM kinase activity (Angele et al., 2003; Austen et al., 2008; Barone et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the heterozygous state in individuals with breast or prostate cancer in published literature (Aloraifi et al., 2015; Matejcic et al., 2020; Darst et al., 2021); This variant is associated with the following publications: (PMID: 26354930, 29117359, 28580595, 29038235, 29625052, 19431188, 21792198, 21933854, 15101044, 22529920, 16014569, 23585524, 18573109, 16189143, 10817650, 22649200, 27479817, 27542854, 21459046, 25480502, 9872980, 26681312, 29482223, 28767289, 30549301, 32866655, 23532176, 34687117, 32980694, 32853339, 32832836, 26094658, 26896183, 29922827, 12552566) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2022	This missense variant replaces arginine with cysteine at codon 3008 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported the variant protein to be defective in ATM kinase activity and cellular response to ionizing radiation exposure (PMID: 12552566, 18573109, 19431188). This variant has been observed in homozygous and compound heterozygous state in multiple individuals affected with ataxia-telangiectasia (PMID: 9872980, 10817650, 12552566, 18573109, 21459046, 21792198). This variant also has been observed in three individuals affected with breast cancer (PMID: 26681312, 30128536) and another individual at high-risk for breast and ovarian cancer (PMID: 26094658). This variant has been identified in 4/251428 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2022	The p.R3008C pathogenic mutation (also known as c.9022C>T) is located in coding exon 62 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 9022. The arginine at codon 3008 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported both in trans with pathogenic splice site mutations and also homozygous in a patient with classic ataxia-telangiectasia (Hacia J et al. Genome Res. 1998 Dec; 8(12):1245-58; Li A and Swift M. Am J Hum Genet. 2000 May 29; 92(3):170-7; Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). A study of 104 Irish cases of hereditary breast cancer identified this alteration in one case (Aloraifi F et al., FEBS J. 2015 Sep; 282(17):3424-37). This alteration was also identified in 1 individual with breast cancer in a study of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). This alteration impacts a highly-conserved residue in the ATM kinase domain and functional studies of this alteration have demonstrated complete loss of kinase activity both in vitro and in vivo (Angele S et al. Hum Mutat. 2003 Feb; 21(2):169-70). In addition, p.R3008C has been associated with reduced ATM protein levels, radiosensitivity levels similar to truncating mutations, and interference with endogenous ATM protein (Gutierrez-Enriquez S et al. Genes Chromosomes Cancer. 2004 Jun; 40(2):109-19; Barone G et al. Hum Mutat. 2009 Aug; 30(8):1222-30). Another missense alteration at this codon (p.R3008H) has been described as a likely deleterious allele detected in 1/122 familial breast cancer cases, 0/186 healthy control samples (Paglia L et al. Breast Cancer Res Treat. 2010 Jan; 119(2):443-52). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 19, 2020	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 06, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12552566, 18573109, 23585524]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9872980, 12552566, 22649200]. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.75
MutPred		0.84		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);
MVP		0.97
MPC		0.67
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs587782292; hg19: chr11-108236086; COSMIC: COSV53730980; COSMIC: COSV53730980;