11-108272532-G-T

Position:

chr11-108272532-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000051.4(ATM):c.3078G>T(p.Trp1026Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,456,784 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense, splice_region

Scores

Splicing: ADA: 0.9980

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.59

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108272532-G-T is Pathogenic according to our data. Variant chr11-108272532-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.3078G>T	p.Trp1026Cys	missense_variant, splice_region_variant	21/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.3078G>T	p.Trp1026Cys	missense_variant, splice_region_variant	21/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251078

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456784

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 18, 2024	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23726790, 28126470]. -

Ataxia-telangiectasia syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1026 of the ATM protein (p.Trp1026Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 23726790, 28126470). 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: 234132). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The c.3078G>T pathogenic mutation (also known as p.W1026C) is located in coding exon 20 of the ATM gene. The tryptophan at codon 1026 is replaced by cysteine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 20. This alteration has been reported in conjunction with other ATM alterations in individuals affected with ataxia-telangiectasia (Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7; van Os NJH et al. Clin Immunol, 2017 05;178:45-55; van Os NJH et al. J Neurol, 2020 Mar;267:830-837). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358).This alteration was also reported in 5/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Oct 08, 2024

According to the ClinGen ACMG ATM v1.3.0 criteria we chose these criteria: PVS1 (very strong pathogenic): Eigene RNA-Analysen (37640): Skipping von Exon 21, . frame shift, monoallelische Expression, r.3078_3153del, p.(His1027Leufs*12), PM2 (supporting pathogenic): Grpmax Filtering AF = 6.215e-7, PM3 (strong pathogenic): Chen (2013, PMID: 23726790): phenotype confident but phase unknown --> 2 P van Os (2017 & 2020, PMID: 28126470 & 31776720): phenotype confident but phase unknown --> 2 P -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.23

.;T;T

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;T;.

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.57

D;D;D

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.7

.;L;L

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Benign

0.28

Sift

Benign

0.15

T;T;T

Sift4G

Pathogenic

0.0

D;T;T

Polyphen

0.17

.;B;B

Vest4

0.40, 0.38

MutPred

0.74

Loss of MoRF binding (P = 0.0494);Loss of MoRF binding (P = 0.0494);Loss of MoRF binding (P = 0.0494);

MVP

0.92

MPC

0.20

ClinPred

0.37

GERP RS

5.4

Varity_R

0.61

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.70

Position offset: 0

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