11-108227594-G-T

Variant names:

• chr11-108227594-G-T
• rs869312754
• NM_000051.4:c.-30-1G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000051.4(ATM):​c.-30-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 3.30

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011122015 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of 4, new splice context is: tgtattttttttacatacAGtga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108227594-G-T is Pathogenic according to our data. Variant chr11-108227594-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224517.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.-30-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.-30-1G>T		splice_acceptor_variant, intron_variant	Intron 1 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2 Uncertain:1

Jun 22, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to T nucleotide substitution at the -1 position of intron 1 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have reported that this variant leads to multiple aberrant RNA transcripts (PMID: 26845104, 31843900). One transcript deletes the exon 2, including the translation start codon, of the ATM gene. This aberrant transcript is expected to result in an absent or non-functional protein product. The other transcript contains a deletion of 4 nucleotides in the 5′ untranslated region (c.-30_-27del). The impact of this transcript on the ATM protein expression is unclear. This variant has been reported in an individual affected with breast and ovarian cancer (PMID: 26845104). 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. It is however important to note that due to the incomplete impact on RNA splicing, the associated cancer risk may be different from other pathogenic ATM variants. Medical management should be considered based on the individual’s personal and family history. -

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-30-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 1 of the ATM gene. This alteration has been identified in an individual diagnosed with breast and ovarian cancers and was reported to cause skipping of coding exon 1 (Shirts BH et al. Genet. Med. 2016 10;18:974-81). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration causes skipping of coding exon 1, but also activates a cryptic acceptor site 4 nucleotides downstream from the native site (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A. 2019 Dec; Ambry internal data). The resulting transcript from this cryptic acceptor site removes only 4 nucleotides from the 5'UTR; the clinical relevance of the loss of these nucleotides is unknown at this time. Based on the available evidence, the clinical significance of this variant remains unclear. -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:2

Sep 01, 2019

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 17, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate aberrant splicing resulting in multiple transcripts including skipping of exon 2 as well as a predominant transcript lacking 4bp in the 5' UTR, the significance of which is unknown (Casadei et al., 2019; External communication with Ambry Genetics); Identified in an individual with personal and family history of ATM-related cancer (Shirts et al., 2016); In silico analysis supports a deleterious effect on splicing; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845104, 31843900) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 5
DS_AL_spliceai		0.86		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs869312754; hg19: chr11-108098321;