11-108345870-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PM2_SupportingPS3_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The ATM c.8546G>C (p.Arg2849Pro) variant has been observed in a compound heterozygous state (presumed) in an individual with biallelic disease and in heterozygosity in an individual with biallelic disease with a second variant unidentified (PM3, PMID:23667852, PMID:9887333). This variant is non-functional in multiple different protein assays (PS3_Moderate, PMID:11805335). In silico protein predictors (ALIGN GVGD: Class C65; REVEL: 0.919; SIFT: damaging; PolyPhen2: probably damaging) predict that this alteration is deleterious (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA382518439/MONDO:0016419/020

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.98

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 Likely_pathogenic. Variant got 6 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8546G>C	p.Arg2849Pro	missense_variant	Exon 58 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8546G>C	p.Arg2849Pro	missense_variant	Exon 58 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727080

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:2

Nov 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2849 of the ATM protein (p.Arg2849Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 9887333, 23667852). ClinVar contains an entry for this variant (Variation ID: 490737). 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: 11805335). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 23, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8546G>C (p.Arg2849Pro) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) 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 251104 control chromosomes. c.8546G>C has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Huh_2013, Sandoval_1999). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal ATM activity and diminished ATM proteins (Scott_2001, Sandoval_1999). The following publications have been ascertained in the context of this evaluation (PMID: 23667852, 9887333, 11805335). ClinVar contains an entry for this variant (Variation ID: 490737). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Sep 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2849P pathogenic mutation (also known as c.8546G>C), located in coding exon 57 of the ATM gene, results from a G to C substitution at nucleotide position 8546. The arginine at codon 2849 is replaced by proline, an amino acid with dissimilar properties. This mutation has been detected in two Korean siblings with ataxia-telangiectasia (AT). A second mutation was also detected in the ATM gene in these siblings, however the phase of these two alterations (cis or trans) was not confirmed (Huh HJ et al. Ann Lab Med, 2013 May;33:217-20). This mutation has also detected as heterozygous in a German patient with AT; however a second alteration in the ATM gene was not identified (Sandoval N et al. Hum. Mol. Genet., 1999 Jan;8:69-79). Functional studies suggest that this alteration disrupts ATM kinase activity and increases radiosensitivity (Scott SP et al. Proc. Natl. Acad. Sci. U.S.A., 2002 Jan;99:925-30). Based on internal structural analysis, this alteration disrupts interactions between the kinase and FAT domains of ATM and is more destabilizing than nearby pathogenic variants (Lavin MF et al. DNA Repair (Amst.);3:1197-205; Bareti D et al. Sci Adv, 2017 May;3:e1700933; Xin J et al. Cell Res., 2019 08;29:655-665). This variant was not reported in population-based 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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 arginine with proline at codon 2849 of the ATM protein. The reference arginine 2849 is invariant and is located in the kinase domain and structural studies on ATM and its yeast homolog have suggested that this variant may affect ATM stabilization (PMID: 28508083, 31097817). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study reported that this variant lacks detectable kinase activity and may act in a dominant-negative fashion to repress wild-type ATM activity (PMID: 11805335). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 23667852, 9887333). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial cancer of breast

Pathogenic:2

Mar 16, 2022

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The ATM c.8546G>C (p.Arg2849Pro) variant has been observed in a compound heterozygous state (presumed) in an individual with biallelic disease and in heterozygosity in an individual with biallelic disease with a second variant unidentified (PM3, PMID: 23667852, PMID: 9887333). This variant is non-functional in multiple different protein assays (PS3_Moderate, PMID: 11805335). In silico protein predictors (ALIGN GVGD: Class C65; REVEL: 0.919; SIFT: damaging; PolyPhen2: probably damaging) predict that this alteration is deleterious (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. -

Sep 19, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Aug 23, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; This variant is associated with the following publications: (PMID: 23667852, 11805335, 15279808, 31097817, 9887333, 22529920, 16652348, 23532176) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;.

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

H;H

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.97

Loss of ubiquitination at K2848 (P = 0.0505);Loss of ubiquitination at K2848 (P = 0.0505);

MVP

0.99

MPC

0.70

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.97

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