rs587781927

Variant names:

• chr11-108293479-T-A
• rs587781927
• NM_000051.4:c.4776+2T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108293479-T-A
• chr11-108293479-T-C
• chr11-108293479-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_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: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.88

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 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
ATM	NM_000051.4	c.4776+2T>A		splice_donor_variant, intron_variant	Intron 31 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4776+2T>A		splice_donor_variant, intron_variant	Intron 31 of 62		NM_000051.4	ENSP00000501606.1

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

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

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

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. -

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. -

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

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. -

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. -

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

Other links and lift over

dbSNP: rs587781927; hg19: chr11-108164206;