11-108353831-G-T

Variant names:

• chr11-108353831-G-T
• rs756899044
• NM_000051.4:c.8737G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.8737G>T​(p.Asp2913Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 10.0

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 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 11-108353831-G-T is Pathogenic according to our data. Variant chr11-108353831-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108353831-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8737G>T	p.Asp2913Tyr	missense_variant	Exon 60 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8737G>T	p.Asp2913Tyr	missense_variant	Exon 60 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727220

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: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Aug 20, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8737G>T (p.Asp2913Tyr) results in a non-conservative amino acid change located in the ATM, catalytic domain (IPR044107) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251460 control chromosomes (gnomAD). c.8737G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Micol_2011, Jacquemin_2012). The variant has also been reported in individuals affected with breast and prostate cancer (e.g. Lu_2019, Dorling_2021, Karlsson_2021). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant results in reduced protein expression, while it alters subcellular localization and cell cycle distribution and it impairs phosphorylation of target proteins such as H2AX, CHK2 and KAP1 (Jacquemin_2012, Fievet_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2913 of the ATM protein (p.Asp2913Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia and/or prostate cancer (PMID: 21665257, 22071889, 33436325). ClinVar contains an entry for this variant (Variation ID: 230841). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATM function (PMID: 22071889, 31050087). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 05, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D2913Y variant (also known as c.8737G>T), located in coding exon 59 of the ATM gene, results from a G to T substitution at nucleotide position 8737. The aspartic acid at codon 2913 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with a clinical diagnosis of ataxia-telangiectasia in both homozygous and compound heterozygous states (Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9). Cell lines from an individual with ataxia telangiectasia who was heterozygous for this alteration along with a second alteration in ATM, exhibited decreased response to ionizing radiation, decreased ATM protein expression, and abnormal cellular localization (Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar;20(3):305-12). Additionally, this alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This variant was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with tyrosine at codon 2913 of the ATM protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Functional studies have shown that this variant results in reduced protein expression, abnormal sub-cellular localization, and disrupted phosphorylation activity (PMID: 22071889, 31050087). This variant has been reported in individuals affected with ataxia-telangiectasia in homozygosity and compound heterozygosity with a known pathogenic co-variant (PMID: 21665257, 31050087). In addition, this variant has been reported in individuals affected with breast cancer (PMID: 28779002, 30128536, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

ATM-related cancer predisposition Pathogenic:1

Jan 30, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Mar 10, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 25122203]. Functional studies indicate this variant impacts protein function [PMID: 22071889, 31050087]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.0	H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.74		Loss of stability (P = 0.098);Loss of stability (P = 0.098);
MVP		0.98
MPC		0.65
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94

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

Other links and lift over

dbSNP: rs756899044; hg19: chr11-108224558; COSMIC: COSV99587069;