rs2229021

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):c.4279G>A(p.Ala1427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,611,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 1.22

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047621906).

BP6

Variant 11-108289644-G-A is Benign according to our data. Variant chr11-108289644-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4279G>A	p.Ala1427Thr	missense_variant	29/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.4279G>A	p.Ala1427Thr	missense_variant	29/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

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:

0.0000281

AC:

AN:

249502

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134926

show subpopulations

Gnomad AFR exome

AF:

0.000248

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:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1458938

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

725574

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

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:

0.0000288

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000337

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:

0.0000282

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1427 of the ATM protein (p.Ala1427Thr). This variant is present in population databases (rs2229021, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, prostate cancer (PMID: 17333338, 19781682, 34326862, 35047863, 35666082). ClinVar contains an entry for this variant (Variation ID: 141884). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 14, 2020	- -

Familial cancer of breast

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Oct 29, 2019	This variant has been reported in the literature in individuals with breast cancer (Hirsch 2008, Tavtigian 2009). This variant has an overall allele frequency of 0.00003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	ATM (c.4279G>A) genes. These variants are missense mutations that substitute one amino acid for another. The current evidence uncertain significance category. Therefore, the diagnosis of hereditary cancer syndrome is not confirmed. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, prostate or pancreatic cancer (PMID: 17333338, 19781682, 34326862, 35666082, 35047863); This variant is associated with the following publications: (PMID: 22529920, 30197789, 19781682, 17333338, 35047863, 34326862, 35666082) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 04, 2024	The p.A1427T variant (also known as c.4279G>A), located in coding exon 28 of the ATM gene, results from a G to A substitution at nucleotide position 4279. The alanine at codon 1427 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 06, 2024

Variant summary: ATM c.4279G>A (p.Ala1427Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was detected at a frequency of 4.3e-05 in 1611184 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.3e-05 vs 0.001), allowing no conclusion about variant significance. The variant was also found in in 2/2559 African American women over the age of 70 without cancer in the FLOSSIES database. c.4279G>A has been reported in the literature in settings of multi-gene panel testing in individuals affected with cancers including, prostate, kidney, ovarian, gastric, womb, melanoma, non-small cell lung cancer, or with personal or family history of breast cancer, all without evidence of causality (e.g. Hirsch_2008, Giri_2022, deOliveira_2022, vanderMerwe_2022, Ricciuti_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17333338, 35666082, 37097610, 35534704, 36568162). ClinVar contains an entry for this variant (Variation ID: 141884). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.30

DEOGEN2

Benign

0.085

T;T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

0.90

D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.11

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;D

Polyphen

0.0020

B;B;.

Vest4

0.045

MVP

0.78

MPC

0.12

ClinPred

0.0086

GERP RS

0.056

Varity_R

0.050

gMVP

0.29

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