11-108309104-G-A

Position:

• chr11-108309104-G-A

Variant summary

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

The NM_000051.4(ATM):​c.5763-1056G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000721 in 1,108,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.159

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 11-108309104-G-A is Pathogenic according to our data. Variant chr11-108309104-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1696413.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5763-1056G>A		intron_variant		ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5763-1056G>A		intron_variant			NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000784 AC: 1 AN: 127508 Hom.: 0 AF XY: 0.0000143 AC XY: 1 AN XY: 69842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000721 AC: 8 AN: 1108962 Hom.: 0 Cov.: 15 AF XY: 0.0000107 AC XY: 6 AN XY: 559224

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: 0.00000843

Gnomad4 OTH exome AF: 0.0000205

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change falls in intron 38 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with breast cancer (PMID: 35806449). ClinVar contains an entry for this variant (Variation ID: 1696413). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 35806449; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. -

ATM-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

This variant has been reported in an individual with breast cancer, and RNAseq studies suggest this variant impacts mRNA splicing (Dragoš et al. 2022. PubMed ID: 35806449). This variant is reported in 0.0021% of alleles in individuals of European (non-Finnish) descent in gnomAD. It has conflicting classifications listed in ClinVar, ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/1696413/). This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

The c.5763-1056G>A intronic variant results from a G to A substitution 1056 nucleotides upstream from coding exon 38 in the ATM gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same cryptic donor site (c.5763-1050A>G) has been shown to have a similar impact on splicing (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stewart GS et al. J. Biol. Chem. 2001 Aug 10;276:30133-41; Ambry internal data) and has been observed in multiple ataxia telangiectasia (AT) cohorts in both the homozygous and compound heterozygous state (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sutton IJ et al. Ann. Neurol. 2004 Jun;55:891-5; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161(3):575-586). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

May 15, 2022

ATM:c.5763-1056G>A variant is present in 0.00078% in the large population studies (GnomAd). The deep intronic variant is predicted to strengthen a cryptic donor splice site in intron 38 by in silico splicing tools. Functional RNA study has shown that the variant causes a splicing aberration - pseudoexon inclusion, causing the creation of a premature stop codon (PMID: 35806449). Since it has not been established whether the variant causes complete or incomplete splicing aberration, the variant was classified as variant of uncertain significance (ACMG/AMP: PM2-supp, PP3, PS3-m) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	18
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.41		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: rs1325461375; hg19: chr11-108179831;