NM_000051.4:c.8786+1G>C

Variant names:

• chr11-108353881-G-C
• rs17174393
• NM_000051.4:c.8786+1G>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.8786+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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 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 11-108353881-G-C is Pathogenic according to our data. Variant chr11-108353881-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108353881-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8786+1G>C		splice_donor_variant, intron_variant	Intron 60 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8786+1G>C		splice_donor_variant, intron_variant	Intron 60 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 24, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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 in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (PMID: 28825054, 28873162); This variant is associated with the following publications: (PMID: 26618343, 28873162, 28825054, 30287823, 33436325, 22071889, 21665257, 36988593, 31050087, 32980694, 36243179, 33309985) -

Nov 08, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.8786+1G>C variant disrupts a canonical splice-donor site and is predicted to interfere with normal ATM mRNA splicing. This variant has been reported in the published literature in an individual with prostate cancer (PMID: 28825054 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -

Familial cancer of breast Pathogenic:2

Oct 10, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 60 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 187060). Studies have shown that disruption of this splice site results in skipping of exon 60 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the ATM protein in which other variant(s) (p.Asp2913Tyr) have been determined to be pathogenic (PMID: 21665257, 22071889, 31050087, 33436325). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8786+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 59 of the ATM gene. This alteration has been identified in an individual with prostate cancer (Abida W et al. JCO Precis Oncol. 2017 Jul;2017). In addition, a different pathogenic mutation at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous individuals diagnosed with ataxia-telangiectasia (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Laake K et al. Hum. Mutat. 2000 Sep;16:232-46). RNA studies showed abnormal splicing in individuals with the c.8786+1G>C alteration (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		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: rs17174393; hg19: chr11-108224608;