11-108345797-CA-CAAA

Variant names:

• chr11-108345797-C-CAA
• rs786203272
• NM_000051.4:c.8476_8477dupAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.8476_8477dupAA​(p.Asn2826LysfsTer32) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2826N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.19
• 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]

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

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108345797-C-CAA is Pathogenic according to our data. Variant chr11-108345797-C-CAA is described in ClinVar as Pathogenic. ClinVar VariationId is 186852.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.8476_8477dupAA	p.Asn2826LysfsTer32	frameshift	Exon 58 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8476_8477dupAA	p.Asn2826LysfsTer32	frameshift	Exon 59 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-36728_641-36727dupTT		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.8476_8477dupAA	p.Asn2826LysfsTer32	frameshift	Exon 58 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.8476_8477dupAA	p.Asn2826LysfsTer32	frameshift	Exon 59 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*3540_*3541dupAA		non_coding_transcript_exon	Exon 56 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461502 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Mar 22, 2023

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.8476_8477dupAA (p.Asn2826LysfsX32) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251310 control chromosomes. c.8476_8477dupAA has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic_1998). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant has been observed in an individual affected with ataxia-telangiectasia (PMID: 9463314). This variant is also known as insAA at position 8478 in the literature. ClinVar contains an entry for this variant (Variation ID: 186852). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn2826Lysfs*32) in the ATM gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Pathogenic:1

Feb 02, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

Hereditary cancer-predisposing syndrome Pathogenic:1

May 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8476_8477dupAA pathogenic mutation, located in coding exon 57 of the ATM gene, results from a duplication of AA at nucleotide position 8476, causing a translational frameshift with a predicted alternate stop codon (p.N2826Kfs*32). This alteration was reported in a cohort of individuals diagnosed with ataxia-telangiectasia (A-T) (Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62:334-45). Of note, this alteration is also known as 8478 ins AA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs786203272; hg19: chr11-108216524;