rs913665369

Variant names:

• chr11-108301744-T-A
• rs913665369
• NM_000051.4:c.5274T>A

Variant summary

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

The NM_000051.4(ATM):​c.5274T>A​(p.Asp1758Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,464 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.228

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=0.18726552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5274T>A	p.Asp1758Glu	missense_variant	Exon 35 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5274T>A	p.Asp1758Glu	missense_variant	Exon 35 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251176 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135744

Gnomad AFR exome AF: 0.00

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1758E variant (also known as c.5274T>A), located in coding exon 34 of the ATM gene, results from a T to A substitution at nucleotide position 5274. The aspartic acid at codon 1758 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Oct 23, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 1758 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Ataxia-telangiectasia syndrome Uncertain:1

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with glutamic acid at codon 1758 of the ATM protein (p.Asp1758Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.73	T;.
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.23
Sift	Benign	0.21	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.33	B;B
Vest4		0.24
MutPred		0.41		Gain of helix (P = 0.0143);Gain of helix (P = 0.0143);
MVP		0.82
MPC		0.13
ClinPred		0.18	T
GERP RS		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.34

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: rs913665369; hg19: chr11-108172471; COSMIC: COSV53742215; COSMIC: COSV53742215;