11-108267171-G-T

Position:

• chr11-108267171-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000051.4(ATM):​c.2467G>T​(p.Ala823Ser) variant causes a missense, splice region 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.3189
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.92

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15381494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.2467G>T	p.Ala823Ser	missense_variant, splice_region_variant	17/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2467G>T	p.Ala823Ser	missense_variant, splice_region_variant	17/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 04, 2022

This variant is not present in population databases (gnomAD no frequency). 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 186370). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 823 of the ATM protein (p.Ala823Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2023

Not 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 submitter

clinical testing

Ambry Genetics

Sep 30, 2014

The p.A823S variant (also known as c.2467G>T) is located in coding exon 16 of the ATM gene. The alanine at codon 823 is replaced by serine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 16 which makes it likely to have some effect on normal mRNA splicing. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficacy of the native acceptor splice site, but is not predicted to have a deleterious effect on this acceptor splice site by BDGP; however, direct evidence is unavailable. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 22000 alleles tested) in our clinical cohort. 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 p.A823S remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	.;T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.071	T;T;T
Polyphen		0.0050	.;B;B
Vest4		0.15, 0.11
MutPred		0.39		Gain of disorder (P = 0.0203);Gain of disorder (P = 0.0203);Gain of disorder (P = 0.0203);
MVP		0.76
MPC		0.11
ClinPred		0.32	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.32
dbscSNV1_RF	Benign	0.50
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

Other links and lift over

dbSNP: rs786202895; hg19: chr11-108137898;