11-108301698-C-T

Position:

chr11-108301698-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000051.4(ATM):c.5228C>T(p.Thr1743Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000638 in 1,613,538 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 (★★).

Frequency

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

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 6.50

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 11-108301698-C-T is Pathogenic according to our data. Variant chr11-108301698-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127403.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 link	c.5228C>T	p.Thr1743Ile	missense_variant	35/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.5228C>T	p.Thr1743Ile	missense_variant	35/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251178

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461478

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727058

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:

0.0000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00008476 (0.008%; 100/1179784 alleles in European non Finnish population). PM3_strong: 3 points awarded for 3 observations of variant with pathogenic variants confirmed in trans (PMID: 31921190, 19147735, 9463314). PP3_moderate: REVEL score is 0.83. PS3_supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product. PS4 not evaluated as affected literature probands with variant already counted under PM3. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 21, 2024	Variant summary: ATM c.5228C>T (p.Thr1743Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251178 control chromosomes. c.5228C>T has been reported in the literature in individuals affected with ataxia-telangiectasia, including at-least two cases being identified in trans with differenct pathogenic variants (example, Mandola_FI_2019, Mantravadi_2021, Jackson_2016 ). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity and ATM expression in vitro (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 26896183, 31921190, 34539671). ClinVar contains an entry for this variant (Variation ID: 127403). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1743 of the ATM protein (p.Thr1743Ile). This variant is present in population databases (rs587779844, gnomAD 0.004%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 9463314, 17968022, 19147735, 19781682, 21792198, 21933854, 27978560, 30303537, 31921190). 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: 127403). 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: 19431188). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Apr 12, 2018	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 14, 2020	PM3_Strong, PS3_moderate, PS4_moderate, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2018	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2023	Observed in the heterozygous state in individuals with a personal or family history including breast, pancreatic, and other cancers (PMID: 19781682, 30303537, 27978560, 21933854, 35047863); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21792198, 21787400, 17968022, 26582918, 19431188, 20346647, 21933854, 22529920, 27978560, 30549301, 19147735, 30303537, 9463314, 19781682, 32832836, 34771661, 33436325, 32853339, 35078243, 34539671, 26896183, 31921190, 35047863, 29922827, 33471991, 36623239, 34326862, 26898890, 37712079, 28779002, 16014569) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 2022	The p.T1743I variant (also known as c.5228C>T), located in coding exon 34 of the ATM gene, results from a C to T substitution at nucleotide position 5228. The threonine at codon 1743 is replaced by isoleucine, an amino acid with similar properties. Multiple individuals with ataxia telangiectasia have been found to carry this alteration in combination with a truncating ATM mutation; however, phase of the alterations was not determined (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Nahas SA et al. Clin Chem, 2009 Mar;55:463-72; Mandola AB et al. Front Immunol, 2019 Dec;10:2940; Jackson TJ et al. Dev Med Child Neurol 2016 07;58(7):690-7). Subsequently, cells from one of these patients were shown to express low levels of mutant protein but did not display any ATM kinase activity based on immunoblotting following irradiation (Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91). Another study evaluating kinase activity found that this alteration resulted in reduced, but not eliminated, phosphorylation of downstream targets compared to positive controls (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has been detected in multiple breast cancer patients across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was 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 alteration was identified in the germline of one patient with chronic lymphocytic leukemia in conjunction with loss of heterozygosity at chromosome 11q (Skowronska A et al. Haematologica. 2012 Jan;97:142-6). Computational analyses using in silico tools classify this variant as having unknown or borderline potential for pathogenicity (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; George Priya Doss C et al. PLoS One. 2012 Apr;7:e34573). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 30, 2023	This missense variant replaces threonine with isoleucine at codon 1743 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 reported that this variant protein had reduced kinase activity in a cell-based assay (PMID: 19431188). This variant has been reported in the compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9463314, 21792198, 31921190). This variant has also been reported in individuals affected with breast cancer (PMID: 19781682, 28779002, 30303537, 33471991), prostate cancer (PMID: 33436325), and colon cancer (PMID: 27978560) and has been reported to segregate with breast cancer in one family (Tischkowitz et al. ESMO Preceptorship on Hereditary Cancer Genetics 2019). This variant has been identified in 5/282558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31921190,19147735, 26896183, 9463314, 37438524]. Functional studies indicate this variant impacts protein function [PMID: 19431188, 26896183, 9463314]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;T

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.86

D;.

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.79

Gain of ubiquitination at K1744 (P = 0.0898);Gain of ubiquitination at K1744 (P = 0.0898);

MVP

0.96

MPC

0.31

ClinPred

0.91

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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