11-108301674-C-T

Position:

• chr11-108301674-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.5204C>T​(p.Thr1735Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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
• Conservation: PhyloP100: 2.60

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=0.30041692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5204C>T	p.Thr1735Ile	missense_variant	35/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5204C>T	p.Thr1735Ile	missense_variant	35/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 27, 2020

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5204C>T, in exon 35 that results in an amino acid change, p.Thr1735Ile. This sequence change does not appear to have been previously described in patients with ATM-related disorders and has also not been described in population databased (gnomAD, ExAC). The p.Thr1735Ile change affects a poorly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Thr1735Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr1735Ile change remains unknown at this time. -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1735 of the ATM protein (p.Thr1735Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2024

The p.T1735I variant (also known as c.5204C>T), located in coding exon 34 of the ATM gene, results from a C to T substitution at nucleotide position 5204. The threonine at codon 1735 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. 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	0.087
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T;T
Eigen	Benign	0.064
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.12
Sift	Benign	0.16	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.38	B;B
Vest4		0.32
MutPred		0.43		Gain of stability (P = 0.0417);Gain of stability (P = 0.0417);
MVP		0.82
MPC		0.13
ClinPred		0.71	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.22
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108172401;