rs587778071

Positions:

• chr11-108272593-A-G
• chr11-108272593-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000051.4(ATM):​c.3139A>G​(p.Lys1047Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 4.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18294922).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.3139A>G	p.Lys1047Glu	missense_variant	21/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.3139A>G	p.Lys1047Glu	missense_variant	21/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2021

- -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2024

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2023

The p.K1047E variant (also known as c.3139A>G), located in coding exon 20 of the ATM gene, results from an A to G substitution at nucleotide position 3139. The lysine at codon 1047 is replaced by glutamic acid, an amino acid with similar properties. This variant was identified in a cohort of individuals diagnosed with breast cancer (Xie Y et al. Clin Genet, 2018 Jan;93:41-51). 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 Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.068	.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T;D;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.6	.;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.45	T;T;T
Sift4G	Uncertain	0.013	D;T;T
Polyphen		0.012	.;B;B
Vest4		0.53, 0.55
MutPred		0.41		Loss of ubiquitination at K1047 (P = 0.021);Loss of ubiquitination at K1047 (P = 0.021);Loss of ubiquitination at K1047 (P = 0.021);
MVP		0.77
MPC		0.21
ClinPred		0.43	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.21

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

Other links and lift over

dbSNP: rs587778071; hg19: chr11-108143320;