11-108289759-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (LINK:https://erepo.genome.network/evrepo/ui/classification/CA298357/MONDO:0016419/020

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 7.71

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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.4394T>C	p.Leu1465Pro	missense_variant	Exon 29 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.4394T>C	p.Leu1465Pro	missense_variant	Exon 29 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251106

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:4

Jun 06, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1465 of the ATM protein (p.Leu1465Pro). This variant is present in population databases (rs730881391, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia, esophageal cancer, gastric cancer, and/or prostate cancer (PMID: 10234507, 26681312, 26896183, 32853339, 33436325, 37232349). 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: 181996). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 10234507, 19431188). 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. -

Oct 30, 2015

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: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 4/4 in silico tools predict damaging outcome for this substitution. Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM variant (0.4%). The variant was reported in one A-T patient (Izatt_EJHG_1999) who was compound heterozygote for the variant of interest and a potentially deleterious frameshift/truncating variant 1355delC; p.Thr452Asnfs indicating the variant to have a role in A-T pathology. Furthermore, Izatt_EJHG_1999 showed the variant to result in low level of ATM expression indicating that the L1465P missense mutation may lead to instability of the protein. Additionally, Barone_Hum Mutat_2009 reported the L1465P ATM variant to have reduced kinase activity toward its downstream targets providing an independent support for the pathogenicity of the variant. A clinical laboratory classifies variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate) and HGMD lists variant with a classification of Disease Mutation. Considering all evidence, the variant is classified as Likely Pathogenic. -

Familial cancer of breast

Pathogenic:2

Jan 25, 2024

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 c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (</=0.001%) for PM2_Supporting, meeting this criterion. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 9463314, 10234507, 26896183). The computational predictor, Revel (Score: 0.802), predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PM2_supporting, PM3_strong, PP3). -

Sep 12, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Oct 29, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate reduced kinase activity (PMID: 19431188); Identified in individuals with breast or prostate cancer and segregates with breast cancer in at least one family (PMID: 32853339, 33436325, 37232349); 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: 27304073, 22529920, 26681312, 29308099, 29922827, 10234507, 26896183, 27153395, 33436325, 32853339, 37232349, 19431188) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 21, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L1465P variant (also known as c.4394T>C), located in coding exon 28 of the ATM gene, results from a T to C substitution at nucleotide position 4394. The leucine at codon 1465 is replaced by proline, an amino acid with very few similar properties. This variant has been identified in a compound heterozygous state in an Irish individual with ataxia-telangiectasia (A-T). Functional analysis indicated low levels of ATM expression (1%) suggesting that this alteration likely changes the secondary structure of the protein as the proline substitution is located in the middle of a predicted α-helix from amino acids 1460 to 1476 (Izatt L et al. Eur. J. Hum. Genet. 1999 Apr; 7(3):310-20). An additional report suggests this alteration results in reduced kinase activity. Authors note that 8 of the 10 ATM variants in this study with reduced kinase activity were identified in A-T patients with a milder A-T phenotype, but do not specify which 8 (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This variant was reported in 10/5560 prostate cancer cases and in 2/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol. 2021 Aug;4:570-579). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability; however, the impact on protein function is not clear (Ambry internal data; Bareti D et al. Sci Adv. 2017 May;3(5):e1700933). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;D;T

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

T;.;T

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

-0.060

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.6

D;D;.

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.99

MutPred

0.88

Loss of stability (P = 0.0251);Loss of stability (P = 0.0251);.;

MVP

0.98

MPC

0.73

ClinPred

1.0

GERP RS

5.6

Varity_R

0.87

gMVP

0.89

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over