chr11-108332037-G-C

Position:

• chr11-108332037-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

The NM_000051.4(ATM):​c.7788G>C​(p.Glu2596Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2596E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 6.76

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 1 ACMG points.

• PP5: Variant 11-108332037-G-C is Pathogenic according to our data. Variant chr11-108332037-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558043.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.7788G>C	p.Glu2596Asp	missense_variant, splice_region_variant	52/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.7788G>C	p.Glu2596Asp	missense_variant, splice_region_variant	52/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461294 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant in c.7788G>C(p.Glu2596Asp) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu2596Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Glu at position 2596 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu2596Asp in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 25, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.7788G nucleotide in the ATM gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9536098, 9792409, 17576681, 26693373; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 558043). This missense change has been observed in individual(s) with ataxia telangiectasia (PMID: 35260754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 2596 of the ATM protein (p.Glu2596Asp). This variant also falls at the last nucleotide of exon 52, which is part of the consensus splice site for this exon. -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 2023	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35260754]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 31, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2023

Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9792409, 23532176, 35260754) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The p.E2596D pathogenic mutation (also known as c.7788G>C), located in coding exon 51 of the ATM gene, results from a G to C substitution at nucleotide position 7788. The glutamic acid at codon 2596 is replaced by aspartic acid, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 51, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in the homozygous state and likely in trans with another ATM variant in individuals diagnosed with ataxia telangiectasia (Ambry internal data; Rawat A et al. Sci Rep, 2022 Mar;12:4036). Another alteration impacting the same donor site (c.7788G>A) has been reported in multiple individuals with a clinical diagnosis of ataxia telangiectasia, two of whom were reported to be homozygous for the mutation (Broeks A et al. Hum. Mutat. 1998;12:330-7; Aygün FD et al. Case Rep Pediatr. 2015;2015: 615368). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. 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	0.14
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	0.052
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.67	T;.
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.86	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.41	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.17	B;B
Vest4		0.23
MutPred		0.23		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.86
MPC		0.15
ClinPred		0.58	D
GERP RS		5.4
Varity_R		0.18
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.81		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780639; hg19: chr11-108202764;