11-108301791-T-C

Position:

• chr11-108301791-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.5319+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000205 in 1,461,010 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: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ATM NM_000051.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9645
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.58

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108301791-T-C is Pathogenic according to our data. Variant chr11-108301791-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 479006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5319+2T>C		splice_donor_variant, intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5319+2T>C		splice_donor_variant, intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461010 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726876

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 25, 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. -

Ataxia-telangiectasia syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2019	Variant summary: ATM c.5319+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. Computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245606 control chromosomes (gnomAD). c.5319+2T>C has been reported in the literature in heterozygous state with another pathogenic variant (ATM 5692C>T, R1898X), in an individual affected with Ataxia-Telangiectasia (Magliozzi_2006). Protein expression analysis carried out on cells derived from the patient showed zero ATM protein level (Prodosmo_2013). The variant has also been detected in one breast cancer patient (Hauke_2018). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change affects a donor splice site in intron 35 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia telangiectasia (PMID: 17124347, 23454770). ClinVar contains an entry for this variant (Variation ID: 479006). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 23454770). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Observed with a pathogenic variant apparently on the opposite allele (in trans) in a patient with classical ataxia telangiectasia syndrome and absent ATM protein expression in published literature (Gilad 1996, Magliozzi 2006, Menotta 2012); Observed in individuals with a personal or family history including breast cancer (Hauke 2016); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS37+2T>C; This variant is associated with the following publications: (PMID: 29522266, 17124347, 8845835, 23055520) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 21, 2021	The c.5319+2T>C pathogenic mutation results from a T to C substitution two nucleotides after coding exon 35 of the ATM gene. This alteration has been previously reported (designated as IVS37+2T>C) in a compound heterozygous individual with A-T (with ATM c.5692C>T) (Magliozzi M et al. Dis. Markers. 2006 ;22(4):257-64, Prodosmo A et al.J. Clin. Invest. 2013 Mar;123(3):1335-42). Further, western blot analysis showed no detectable ATM protein, and functional studies on lymphoblastoid cell lines showed a significant decrease in the percentage of mitotic cells with p53 localization at the centrosome, which is directly dependent on ATM function (Prodosmo A et al.J. Clin. Invest. 2013 Mar;123(3):1335-42). This nucleotide position is highly conserved in available vertebrate species. 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 27, 2023	This variant causes a T to C nucleotide substitution at the +2 position of intron 35 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant (also known as IVS37+2T>C in the literature) has been reported in the compound heterozygous state with an additional pathogenic ATM variant in an individual affected with ataxia telangiectasia (PMID: 17124347, 23454770). It has been reported that cells derived from this individual had no detectable ATM protein (PMID: 23454770). This variant has also been reported in at least one individual affected with breast cancer (PMID: 29522266). This variant has not been identified 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 Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		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: rs1555105842; hg19: chr11-108172518; COSMIC: COSV53779770; COSMIC: COSV53779770;