rs730881310

Variant names:

• chr11-108302847-TTCTA-T
• rs730881310
• NM_000051.4:c.5320-5_5320-2delTCTA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.5320-5_5320-2delTCTA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.00000275 in 1,454,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000277203: A-T individuals with at least one copy of this mutation are reported to have no detectable ATM protein (Eng L et al, Hum. Mutat. 2004 Jan" and additional evidence is available in ClinVar. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.14
• Publications: 1 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]

ATM Gene-Disease associations (from GenCC):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019299967 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8, offset of 7, new splice context is: aatccctttcttgtttttAGaag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000277203: A-T individuals with at least one copy of this mutation are reported to have no detectable ATM protein (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). The c.5320-5_5320-2delTCTA mutation has also been reported to cause aberrant splicing that results in the removal of 7 coding nucleotides from coding exon 35, and a transcript that is expected to trigger nonsense-mediated mRNA decay (Eng L et al, Hum. Mutat. 2004 Jan; 23(1):67-76). RNA studies have demonstrated that this alteration results in the same aberrant splicing event reported in the literature (Ambry internal data).; SCV001347420: A functional RNA study (PMID: 14695534) has shown that this variant leads to the use of a cryptic splice acceptor site, resulting in a deletion of the first 7 nucleotides of exon 36 (also known as exon 38 in the literature). This variant is expected to create a frameshift and premature translation stop signal, resulting in an absent or non-functional protein product. There was no detectable ATM protein expression in lymphoblastoid cell lines isolated from at least one affected individual (PMID: 14695534).; SCV000282988: Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 14695534; internal data).; SCV001426884: The most pronounced variant effect results in <10% of normal activity (Gilad_1996).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108302847-TTCTA-T is Pathogenic according to our data. Variant chr11-108302847-TTCTA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 181881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.5320-5_5320-2delTCTA		splice_acceptor splice_region intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.5320-5_5320-2delTCTA		splice_acceptor splice_region intron	N/A	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.5320-5_5320-2delTCTA		splice_acceptor splice_region intron	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.5320-5_5320-2delTCTA		splice_acceptor splice_region intron	N/A	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*384-5_*384-2delTCTA		splice_acceptor splice_region intron	N/A	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454692 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 724248

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105982

Other (OTH) AF: 0.00 AC: 0 AN: 60118

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Ataxia-telangiectasia syndrome (4)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Familial colorectal cancer type X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: 13
DS_AL_spliceai		0.99		Position offset: 6

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

Other links and lift over

dbSNP: rs730881310; hg19: chr11-108173574;