rs587781414

Positions:

• chr11-108335953-A-G
• chr11-108335953-A-T

Variant summary

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

The NM_000051.4(ATM):​c.8260A>G​(p.Thr2754Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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:5
• Conservation: PhyloP100: 4.94

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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8260A>G	p.Thr2754Ala	missense_variant	56/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8260A>G	p.Thr2754Ala	missense_variant	56/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 26, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2022	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 alanine, which is neutral and non-polar, at codon 2754 of the ATM protein (p.Thr2754Ala). ClinVar contains an entry for this variant (Variation ID: 140982). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2022	The p.T2754A variant (also known as c.8260A>G), located in coding exon 55 of the ATM gene, results from an A to G substitution at nucleotide position 8260. The threonine at codon 2754 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved through mammals, but not in lower vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2015

This variant is denoted ATM c.8260A>G at the cDNA level, p.Thr2754Ala (T2754A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2754Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr2754Ala occurs at a position that is conserved in mammals and is located in the PI3K/PI4K domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Thr2754Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.60
Sift	Benign	0.16	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.93	P;P
Vest4		0.62
MutPred		0.54		Gain of MoRF binding (P = 0.103);Gain of MoRF binding (P = 0.103);
MVP		0.96
MPC		0.53
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.58

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: rs587781414; hg19: chr11-108206680; COSMIC: COSV99587714; COSMIC: COSV99587714;