11-108310255-C-T

Position:

chr11-108310255-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS3_SupportingPM3PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5858C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1953 (p.Thr1953Ile). This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID:18634022, 26896183). This variant is absent from gnomAD v2.1.1. Additionally, experimental studies showed that this variant impacts ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID:18634022). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_supporting, PS3_supporting, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA166228/MONDO:0700270/020

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:2

Conservation

PhyloP100: 7.28

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5858C>T	p.Thr1953Ile	missense_variant	39/63	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.5858C>T	p.Thr1953Ile	missense_variant	39/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726950

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 19, 2024	The p.T1953I variant (also known as c.5858C>T) is located in coding exon 38 of the ATM gene. This alteration results from a C to T substitution at nucleotide position 5858. The threonine at codon 1953 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in conjunction with a pathogenic ATM variant, c.8786+1G>A, in one individual from the UK diagnosed with ataxia-telangiectasia (AT) (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). This alteration was also reported in conjunction with another ATM alteration, p.W2109G, in an individual diagnosed with atypical AT who presented with truncal ataxia and telangiectasia since childhood (Mitui, M et al. Hum Mutat. 2009 Jan;30(1):12-21). Functional studies performed by Mitui et al. showed reduced expression and intermediate radiosensitivity, and led the authors to conclude that this alteration is most likely a "kinase-impaired" protein. This alteration has been identified in at least one patient with a personal and family history of breast, ovarian cancer, and prostate cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 26, 2022	This missense variant replaces threonine with isoleucine at codon 1953 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in significantly reduced ATM protein expression and function in vitro (PMID: 18634022). This variant has been observed in an adult individual affected with mild ataxia-telangiectasia phenotype, who also carried a p.Trp2109Gly variant in the same gene (PMID: 18634022). The p.Trp2109Gly variant did not show a deleterious effect on the ATM Protein function (PMID: 18634022). This variant has also been reported in an individual affected with prostate cancer (PMID: 31214711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 13, 2021	- -

Ataxia-telangiectasia syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1953 of the ATM protein (p.Thr1953Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or ATM-related cancers (PMID: 18634022, 25186627, 26896183, 31214711). ClinVar contains an entry for this variant (Variation ID: 141721). 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. 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. Experimental studies have shown that this missense change affects ATM function (PMID: 18634022). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 19, 2024	Variant summary: ATM c.5858C>T (p.Thr1953Ile) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) 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 251084 control chromosomes. c.5858C>T has been reported in the literature in compound heterozygosity with other ATM variants in at-least two individuals affected with Ataxia-Telangiectasia (examples, Mitui_2009, Jackson_2016) and as a VUS in settings of multigene panel testing in one individual affected with breast cancer (example, Tung_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, it was not possible to definitively demonstrate whether the lack of ATM functions was due to reduced ATM protein or leaky expression of a "kinase-impaired" protein (Mitui_2009). The following publications have been ascertained in the context of this evaluation (PMID: 26896183, 18634022, 25186627). ClinVar contains an entry for this variant (Variation ID: 141721) and at-least three peer submitters have classified the variant as Likely Pathogenic, two of whom cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, pending additional clinical evidence supporting an unequivocal association with Ataxia-Telangiectasia, the variant was classified as likely pathogenic. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 26, 2024

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 12, 2024

The ATM c.5858C>T (p.Thr1953Ile) variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2017)) and prostate cancer (PMID: 31214711 (2020)). This variant has been identified in individuals with ataxia-telangiectasia (AT) who also carried other pathogenic ATM variants (PMID: 18634022 (2009), 26896183 (2016)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 18634022 (2009)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

ATM-related cancer predisposition

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Nov 26, 2024

The c.5858C>T variant in ATM is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 1953 (p.Thr1953Ile). This variant has been detected in at least 2 individuals with Ataxia-Telangiectasia (PMID: 18634022, 26896183). This variant is absent from gnomAD v2.1.1. Additionally, experimental studies showed that this variant impacts ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). The computational predictor REVEL gives a score of 0.85, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3, PM2_supporting, PS3_supporting, PP3) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.86

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.98

MPC

0.60

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.83

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