rs863224578

Variant summary

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

The NM_000051.4(ATM):​c.6757A>C​(p.Lys2253Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2253E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Consequence

ATM
NM_000051.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.52
Variant links:
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]

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ACMG classification

Classification made for transcript

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 UniProt
ATMNM_000051.4 linkuse as main transcriptc.6757A>C p.Lys2253Gln missense_variant 46/63 ENST00000675843.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.6757A>C p.Lys2253Gln missense_variant 46/63 NM_000051.4 P1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2016This sequence change replaces lysine with glutamine at codon 2253 of the ATM protein (p.Lys2253Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. 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. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 10, 2019The p.K2253Q variant (also known as c.6757A>C), located in coding exon 45 of the ATM gene, results from an A to C substitution at nucleotide position 6757. The lysine at codon 2253 is replaced by glutamine, an amino acid with similar properties. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.049
T;T
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.89
D;.
M_CAP
Benign
0.083
D
MetaRNN
Uncertain
0.48
T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
D;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.21
Sift
Benign
0.084
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.92
P;P
Vest4
0.43
MutPred
0.73
Loss of ubiquitination at K2253 (P = 0.0218);Loss of ubiquitination at K2253 (P = 0.0218);
MVP
0.87
MPC
0.18
ClinPred
0.82
D
GERP RS
5.3
Varity_R
0.20
gMVP
0.23

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863224578; hg19: chr11-108196221; API