chr11-108289730-T-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.4365T>A(p.Ser1455Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.98

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13842756).

BP6

Variant 11-108289730-T-A is Benign according to our data. Variant chr11-108289730-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186032.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}. Variant chr11-108289730-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.4365T>A	p.Ser1455Arg	missense_variant	Exon 29 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.4365T>A	p.Ser1455Arg	missense_variant	Exon 29 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152232

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:

0.000769

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:

0.00000398

AC:

AN:

251188

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135774

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:

0.0000363

AC:

AN:

1461434

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00134

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

AF:

0.0000263

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:1Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jan 04, 2019

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. -

Jul 28, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with arginine at codon 1455 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies reported loss of kinase activity in irradiated cells and a failure to complement cell survival phenotypes in ATM-defective cells (PMID: 12969974, 29059438). This variant has been reported in individuals affected with Hodgkin lymphoma and neuroblastoma (PMID: 12969974, 29059438). This variant has been identified in 1/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in control individuals (PMID: 12969974, 29059438). 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. -

not provided

Uncertain:1

Jun 25, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30287823, 28779002, 21910157, 12969974, 29059438) -

Hereditary breast ovarian cancer syndrome

Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified

Benign:1

Nov 15, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.4365T>A (p.Ser1455Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 298850 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0031 within the Japanese subpopulation (Takagi_2004, Momozawa_2018). The observed variant frequency within Japanese control individuals is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism. c.4365T>A has been reported in the literature in individuals affected with cancer including pediatric Hodgkin disease, neuroblastoma, breast, prostate and colorectal cancer (Takagi_2004, Decker_2017, Takagi_2017, Momozawa_2018, Fujita_2022, So_2022). However, case-control studies in Japanese individuals have also identified the variant in high frequency in controls and concluded it to be benign (Momozawa_2018, Fujita_2022). Co-occurrences with pathogenic variants have been reported via internal testing (MSH2 c.1204C>T, p.Gln402X; BRCA1 c.5467+1G>A), providing supporting evidence for a benign role. Experimental evidence demonstrated the variant to have an impact on protein function, however, do not allow convincing conclusions about the variant effect (Takagi_2017). Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;.;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

N;N;.

REVEL

Benign

0.12

Sift

Benign

0.069

T;T;.

Sift4G

Uncertain

0.052

T;T;T

Polyphen

0.68

P;P;.

Vest4

0.43

MutPred

0.36

Gain of MoRF binding (P = 0.0197);Gain of MoRF binding (P = 0.0197);.;

MVP

0.82

MPC

0.16

ClinPred

0.71

GERP RS

4.4

Varity_R

0.32

gMVP

0.26

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

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