11-108293479-T-C

Position:

• chr11-108293479-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_000051.4(ATM):​c.4776+2T>C variant causes a splice donor change. The variant allele was found at a frequency of 0.000000687 in 1,455,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor
• Scores: Splicing: ADA: 0.9934
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 6.88

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017882455 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 11-108293479-T-C is Pathogenic according to our data. Variant chr11-108293479-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141672.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.4776+2T>C		splice_donor_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4776+2T>C		splice_donor_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249594 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135048

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455110 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 24, 2018	Variant summary: ATM c.4776+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 244642 control chromosomes. c.4776+2T>C has been reported in the literature in at least two individuals affected with Ataxia-Telangiectasia, one of whom is homozygous for the variant with classic A-T with microcephaly and intellectual disability (Gilad_1998). These data indicate that the variant may be associated with disease. Gilad et al. also report experimental evidence suggesting a loss of ATM protein product in the patient's fibroblast cell line, though the data was not presented for review. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Furthermore, c.4776+2T>A has also been reported to associate with Ataxia-Telangiectasia. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Feb 17, 2017	The c.4776+2T>C canonical splice donor site variant is predicted to cause abnormal gene splicing. This variant, also known as IVS33+2T>C, has been previously reported in the homozygous and compound heterozygous state in individuals with Ataxia-Telangiectasia (AT) (PMID: 9711876). Functional studies showed that this variant led to in-frame skipping of exon 30, previously referred to as exon 32, and a cell line with this variant in the homozygous state exhibited radiosensitivity (PMID: 9497252, 2491181). Based on the combined evidence, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs587781927, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 9497252, 12815592). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS33+2T>C. ClinVar contains an entry for this variant (Variation ID: 141672). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects ATM function (PMID: 2491181, 9497252). Studies have shown that disruption of this splice site results in skipping of exon 31, but is expected to preserve the integrity of the reading-frame (PMID: 9497252; Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 02, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2021	Canonical splice site variant resulting in skipping of exon 31 (Velazquez 2020); Reported in the homozygous and compound heterozygous state in individuals with ataxia-telangiectasia (Curry 1989, Gilad 1998, Mitui 2003); Functional studies showed a cell line with this variant in the homozygous state exhibited radiosensitivity consistent with classic ataxia-telangiectasia cell lines (Curry 1989, Gilad 1998); Observed in the heterozygous state in an individual with a personal and family history of ATM-related cancers (Velazquez 2020); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as IVS33+2T>C; This variant is associated with the following publications: (PMID: 21445571, 12815592, 15279807, 10330348, 25525159, 9497252, 31019026, 32756499, 2491181) -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 24, 2024	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2023	The c.4776+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 30 in the ATM gene. This alteration has previously reported in multiple families with ataxia-telangiectasia, and it has been shown to lead to aberrant splicing with no detectable levels of ATM protein production (Mitui M et al. Hum. Mutat. 2003; 22:43-50; Gilad S et al. Am. J. Hum. Genet. 1998; 62:551-61; Teraoka SN et al. Am. J. Hum. Genet. 1999; 64:1617-31). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Of note, this alteration is also designated as IVS33+2T>C in the published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 21, 2022	This variant causes a T to C nucleotide substitution at the +2 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant leads to the skipping of exon 31, which is expected to result in an in-frame deletion of 55 amino acids (PMID: 9497252, 32756499). Functional studies have shown that the fibroblast cell line derived from a homozygous carrier of this variant exhibits increased radiosensitivity (PMID: 9497252, 2491181). This variant (also known as IVS33+2T>C in the literature) has been reported in the homozygous and compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 12815592, 2491181). This variant has also been reported in an individual affected with breast and ovarian cancer (PMID: 32756499). This variant has been identified in 1/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		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: rs587781927; hg19: chr11-108164206;