11-108259005-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):c.2396C>T(p.Ala799Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A799T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: -0.0370

Publications

10 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_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041645825).

BP6

Variant 11-108259005-C-T is Benign according to our data. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928. Variant chr11-108259005-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 181928.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.2396C>T	p.Ala799Val	missense_variant	Exon 16 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.2396C>T	p.Ala799Val	missense_variant	Exon 16 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152156

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251232

AF XY:

0.0000295

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1111792

Other (OTH)

AF:

0.0000166

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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

AF:

0.0000263

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Aug 21, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nov 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2017

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Nov 20, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25980754, 26689913, 28779002, 31159747) -

Sep 19, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ataxia-telangiectasia syndrome

Uncertain:2

Jul 22, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATM c.2396C>T (p.Ala799Val) missense change has a maximum frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-108129732-C-T). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). This variant has been reported in an individual with renal clear cell carcinoma (PMID: 26689913), an individual with suspected Lynch syndrome (PMID: 25980754), an individual undergoing hereditary cancer syndrome testing (PMID: 31159747), and an unaffected individual (PMID: 30287823). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 799 of the ATM protein (p.Ala799Val). This variant is present in population databases (rs199954262, gnomAD 0.006%). This missense change has been observed in individual(s) with personal and/or family history of cancer (PMID: 26689913, 31159747, 34326862). ClinVar contains an entry for this variant (Variation ID: 181928). 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) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Nov 25, 2019

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATM c.2396C>T (p.Ala799Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 316526 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (3.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2396C>T has been reported in the literature in individuals affected with Lynch syndrome-associated cancer and/or polyps and kidney renal clear cell carcinoma (Yurgelun_2015, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (ATM unspecified variant; MSH2 c.1576del, p.Thr526Profs*17; ATM, exons 61-62 deletion) (Yurgelun_2015, one clinical laboratory), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (4x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Breast and/or ovarian cancer

Uncertain:1

May 16, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant tumor of breast

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ATM p.Ala799Val variant was identified in 1 of 16622 proband chromosomes (frequency: 0.00006) from individuals or families with Lynch syndrome or breast cancer and was present in 4 of 22482 control chromosomes (frequency: 0.0002) from healthy individuals (Momozawa 2018, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs199954262) as "With Uncertain significance allele", ClinVar (classified as likely benign by GeneDx and Ambry Genetics; and as uncertain significance by Invitae and two other submitters), LOVD 3.0 (2x), and in 7 of 277034 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 7 of 126620 chromosomes (freq: 0.00006), but was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala799 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.061

.;T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.71

T;T;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

.;L;L

PhyloP100

-0.037

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.28

N;N;N

REVEL

Benign

0.084

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.76

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.095, 0.077

MutPred

0.27

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);

MVP

0.72

MPC

0.12

ClinPred

0.011

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.12

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over