rs587782497

Positions:

• chr11-108354869-G-A
• chr11-108354869-G-C

Variant summary

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

The NM_000051.4(ATM):​c.8845G>A​(p.Val2949Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 9.96

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.8845G>A	p.Val2949Ile	missense_variant	61/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8845G>A	p.Val2949Ile	missense_variant	61/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460012 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726480

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

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.	Feb 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2949 of the ATM protein (p.Val2949Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 142487). 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. 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	Nov 13, 2023	This missense variant replaces valine with isoleucine at codon 2949 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported as germline in individuals affected with protate cancer (PMID: 33436325) and lung cancer (PMID: 35273153) in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2023	The p.V2949I variant (also known as c.8845G>A), located in coding exon 60 of the ATM gene, results from a G to A substitution at nucleotide position 8845. The valine at codon 2949 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 17, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2018

This variant is denoted ATM c.8845G>A at the cDNA level, p.Val2949Ile (V2949I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant was reported in an individual with splenic marginal zone lymphoma, although germline versus somatic status is unclear (Parry 2015). ATM Val2949Ile was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val2949Ile 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	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.94	L;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.010	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.040	D;D
Sift4G	Benign	0.081	T;T
Polyphen		0.99	D;D
Vest4		0.74
MutPred		0.52		Loss of catalytic residue at V2949 (P = 0.0144);Loss of catalytic residue at V2949 (P = 0.0144);
MVP		0.82
MPC		0.50
ClinPred		0.75	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.60

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: rs587782497; hg19: chr11-108225596;