rs587781712

Positions:

• chr11-108293374-C-A
• chr11-108293374-C-G
• chr11-108293374-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000051.4(ATM):​c.4673C>A​(p.Thr1558Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.11

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27756625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4673C>A	p.Thr1558Lys	missense_variant	31/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4673C>A	p.Thr1558Lys	missense_variant	31/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448016 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721194

Gnomad4 AFR exome AF: 0.00

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2020

This variant has not been reported in the literature in individuals with ATM-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 1558 of the ATM protein (p.Thr1558Lys). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and lysine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2019

The p.T1558K variant (also known as c.4673C>A), located in coding exon 30 of the ATM gene, results from a C to A substitution at nucleotide position 4673. The threonine at codon 1558 is replaced by lysine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.0000 in 7051 unselected breast cancer patients and 0.00018 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.087	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.12
Sift	Benign	0.22	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.24	B;B
Vest4		0.48
MutPred		0.55		Gain of ubiquitination at T1558 (P = 0.017);Gain of ubiquitination at T1558 (P = 0.017);
MVP		0.92
MPC		0.17
ClinPred		0.85	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.55

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: rs587781712; hg19: chr11-108164101; COSMIC: COSV53767118; COSMIC: COSV53767118;