chr11-108309104-G-A

Variant names:

• chr11-108309104-G-A
• rs1325461375
• NM_000051.4:c.5763-1056G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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:4 U:1
• Conservation: PhyloP100: 0.159
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.5763-1056G>A		intron_variant	Intron 38 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5763-1056G>A		intron_variant	Intron 38 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000784 AC: 1 AN: 127508 AF XY: 0.0000143

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 35210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23426

East Asian (EAS) AF: 0.00 AC: 0 AN: 34242

South Asian (SAS) AF: 0.00 AC: 0 AN: 73222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 0.00000843 AC: 7 AN: 830062

Other (OTH) AF: 0.0000205 AC: 1 AN: 48750

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Pathogenic:1 Uncertain:1

May 14, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2022

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Ataxia-telangiectasia syndrome Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 35806449; internal data). For these reasons, this variant has been classified as Pathogenic. -

ATM-related disorder Pathogenic:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.5763-1056G>A variant is predicted to interfere with splicing. 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

Jan 03, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	18
DANN	Benign	0.30
PhyloP100		0.16

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

Other links and lift over

dbSNP: rs1325461375; hg19: chr11-108179831;