rs1555084836

Variant names:

• chr11-108271199-ATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTG-A
• rs1555084836
• NM_000051.4:c.2922-50_2938delGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000051.4(ATM):​c.2922-50_2938delGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT​(p.Asn975fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S974S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.13
• Publications: 0 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):

• hereditary breast carcinoma

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

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

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

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

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-108271199-ATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTG-A is Pathogenic according to our data. Variant chr11-108271199-ATGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 453439.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2922-50_2938delGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTGT	p.Asn975fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 20 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2922-51_2937delTGTGTTCTGTTAAGCTTATAAAGTTGAACTTTTTTTTTTTTTTTACCACAGCAATGTGTGTTCTTTG	p.Asn975fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 20 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Jul 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. Loss-of-function variants including gross deletions in ATM are known to be pathogenic (PMID: 25614872, 23807571). This variant is a gross deletion of the genomic region encompassing part of exon 20 of the ATM gene, including the intron 19-exon 20 boundary (c.2922-50_2938del). This likely creates a premature translational stop signal and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555084836; hg19: chr11-108141926;