rs587781927

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000051.4(ATM):​c.4776+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,455,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.88
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017991494 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108293479-T-A is Pathogenic according to our data. Variant chr11-108293479-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108293479-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATMNM_000051.4 linkc.4776+2T>A splice_donor_variant, intron_variant Intron 31 of 62 ENST00000675843.1 NP_000042.3 Q13315A0A024R3C7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATMENST00000675843.1 linkc.4776+2T>A splice_donor_variant, intron_variant Intron 31 of 62 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1455110
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724322
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000506
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3
Jan 30, 2025
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 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ATM-related conditions (PMID: 9497252, 9600235, 12815592, 31214711, 32566746). ClinVar contains an entry for this variant (Variation ID: 371007). Studies have shown that disruption of this splice site results in skipping of exon 31, also published as exon 33, but is expected to preserve the integrity of the reading-frame (PMID: 9711876). For these reasons, this variant has been classified as Pathogenic. -

Jun 03, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 23, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ATM c.4776+2T>A 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by published functional studies although one report provided indirect evidence supporting the skipping of exon 30 (legacy naming as exon 33) without presenting the data (Sasaki_1998). The variant was absent in 249594 control chromosomes. c.4776+2T>A (reported as 4612del165 or IVS33+2T>A) has been reported in the literature in multiple homozygous and compound heterozygous individuals of Japanese ancestry affected with Ataxia-Telangiectasia (example, Ejima_1998, Sasaki_1998) as well as in reports of Japanese carriers with breast cancer (example, Kaneyasu_2020, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast Pathogenic:2
Jan 04, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2
Feb 24, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes a T to A nucleotide substitution at the +2 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a number of unrelated Japanese individuals affected with breast cancer (PMID: 32566746, 30287823), pancreatic cancer (PMID: 32980694; Color Health internal data), prostate cancer (PMID: 31214711), ataxia-telangiectasia (PMID: 9600235, 9711876), as well as in healthy controls (PMID: 30287823, 32980694). 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. -

Sep 28, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4776+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 30 in the ATM gene. This alteration was seen in multiple, unrelated Japanese patients with ataxia-telangiectasia, and RNA analysis demonstrated that it results in skipping of coding exon 30 (designated as exon 33 in this study) (Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8). In addition, a different ATM mutation at this nucleotide position, c.4776+2T>C, was also seen in patients with ataxia-telangiectasia and was also shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. -

Gastric cancer Pathogenic:1
Jul 01, 2021
Laboratory for Genotyping Development, RIKEN
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1
May 01, 2019
Cancer Genomics Group, Japanese Foundation For Cancer Research
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
31
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.95
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.97
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587781927; hg19: chr11-108164206; API