11-108256225-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000051.4(ATM):​c.2135C>T​(p.Ser712Leu) 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. 16/22 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. S712A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ATM
NM_000051.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Publications

3 publications found
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]
ATM Gene-Disease associations (from GenCC):
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
  • ataxia telangiectasia
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
  • prostate cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • familial ovarian cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • gastric carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.195436).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.2135C>T p.Ser712Leu missense_variant Exon 14 of 63 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.2135C>T p.Ser712Leu missense_variant Exon 14 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1
Dec 11, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has not been reported in the literature in individuals with ATM-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 712 of the ATM protein (p.Ser712Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.090
.;T;T
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.73
T;T;.
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.5
.;L;L
PhyloP100
2.0
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.093
Sift
Benign
0.10
T;T;T
Sift4G
Benign
0.065
T;T;T
Polyphen
0.0
.;B;B
Vest4
0.086, 0.14
MutPred
0.26
Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);Loss of disorder (P = 0.0072);
MVP
0.79
MPC
0.11
ClinPred
0.14
T
GERP RS
2.4
Varity_R
0.079
gMVP
0.17
Mutation Taster
=87/13
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1057516620; hg19: chr11-108126952; API