11-108332838-C-T

Position:

• chr11-108332838-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000051.4(ATM):​c.7865C>T​(p.Ala2622Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2622G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.39

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108332838-C-T is Pathogenic according to our data. Variant chr11-108332838-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.7865C>T	p.Ala2622Val	missense_variant	53/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.7865C>T	p.Ala2622Val	missense_variant	53/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ATM: PM2, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2022	Missense variant that results in aberrant splicing and a null allele in a gene for which loss of function is a known mechanism of disease (Bullrich et al., 1999; Teraoka et al., 1999; Du et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.8250C>T; Missense variant that results in aberrant splicing and a null allele in a gene for which loss of function is a known mechanism of disease (Bullrich et al., 1999; Teraoka et al., 1999; Du et al., 2007); This variant is associated with the following publications: (PMID: 24568663, 33624863, 20945614, 16411093, 10330348, 14695534, 24506781, 18321536, 21576124, 17389389, 9892178, 34426522, 32899500) -

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2622 of the ATM protein (p.Ala2622Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 10330348, 14695534, 16411093, 18321536, 20945614). ClinVar contains an entry for this variant (Variation ID: 449346). 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 tolerated. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10330348, 14695534). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Mar 24, 2022

Gait disorder -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2023

The c.7865C>T pathogenic mutation (also known as p.A2622V), located in coding exon 52 of the ATM gene, results from a C to T substitution at nucleotide position 7865. The alanine at codon 2622 is replaced by valine, an amino acid with similar properties. This alteration has been detected in a homozygous state in multiple individuals with Ataxia Telangiectasia (Teraoka SN et al. Am. J. Hum. Genet., 1999 Jun;64:1617-31; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76; Heinrich T et al. Eur. J. Pediatr., 2006 Apr;165:250-7; Aghamohammadi A et al. J Investig Allergol Clin Immunol, 2010;20:442-5). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA analyses have shown that this alteration creates a new splice donor site, resulting in a deletion of 64 nucleotides from exon 52 and an out of frame transcript (Teraoka SN et al. Am. J. Hum. Genet., 1999 Jun;64:1617-31, Eng L et al. Hum. Mutat., 2004 Jan;23:67-76, Du L et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Apr;104:6007-12, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T;T
Eigen	Benign	0.019
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.83	T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.15	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.38	B;B
Vest4		0.62
MutPred		0.32		Loss of MoRF binding (P = 0.1625);Loss of MoRF binding (P = 0.1625);
MVP		0.83
MPC		0.15
ClinPred		0.74	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs766351395; hg19: chr11-108203565; COSMIC: COSV53756397; COSMIC: COSV53756397;