rs1064795850

Variant summary

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

The NM_000051.4(ATM):​c.3335C>G​(p.Pro1112Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P1112A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ATM
NM_000051.4 missense

Scores

4
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.33
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]

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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.3335C>G p.Pro1112Arg missense_variant 23/63 ENST00000675843.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.3335C>G p.Pro1112Arg missense_variant 23/63 NM_000051.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jun 07, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 17, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1112 of the ATM protein (p.Pro1112Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 422545). -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 02, 2017- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 29, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 24, 2022The p.P1112R variant (also known as c.3335C>G), located in coding exon 22 of the ATM gene, results from a C to G substitution at nucleotide position 3335. The proline at codon 1112 is replaced by arginine, an amino acid with dissimilar properties. This variant identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.091
.;T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D;D;.
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Uncertain
2.9
.;M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.4
N;N;N
REVEL
Uncertain
0.42
Sift
Uncertain
0.012
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.99
.;D;D
Vest4
0.83, 0.84
MutPred
0.41
Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);
MVP
0.92
MPC
0.39
ClinPred
0.89
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Varity_R
0.58
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1064795850; hg19: chr11-108150268; API