11-108307956-G-C

Position:

• chr11-108307956-G-C

Variant summary

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

The NM_000051.4(ATM):​c.5734G>C​(p.Val1912Leu) 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:3
• Conservation: PhyloP100: 4.26

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 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.5734G>C	p.Val1912Leu	missense_variant	38/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5734G>C	p.Val1912Leu	missense_variant	38/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1912 of the ATM protein (p.Val1912Leu). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. ClinVar contains an entry for this variant (Variation ID: 419785). 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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2015

This variant is denoted ATM c.5734G>C at the cDNA level, p.Val1912Leu (V1912L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val1912Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Val1912Leu occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Val1912Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The p.V1912L variant (also known as c.5734G>C), located in coding exon 37 of the ATM gene, results from a G to C substitution at nucleotide position 5734. The valine at codon 1912 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.87	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.14	B;B
Vest4		0.58
MutPred		0.49		Loss of catalytic residue at V1912 (P = 0.007);Loss of catalytic residue at V1912 (P = 0.007);
MVP		0.82
MPC		0.18
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064794105; hg19: chr11-108178683;