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NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Mar 14, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000494628.20

Allele description [Variation Report for NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)]

NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)

Genes:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]
Variant type:
Deletion
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.8876_8879del (p.Asp2959fs)
HGVS:
  • NC_000011.10:g.108365107_108365110del
  • NG_009830.1:g.147276_147279del
  • NG_054724.1:g.109725_109728del
  • NM_000051.4:c.8876_8879delMANE SELECT
  • NM_001330368.2:c.640+20812_640+20815del
  • NM_001351110.2:c.694+20812_694+20815del
  • NM_001351834.2:c.8876_8879del
  • NP_000042.3:p.Asp2959Glyfs
  • NP_000042.3:p.Asp2959fs
  • NP_001338763.1:p.Asp2959fs
  • LRG_135t1:c.8876_8879del
  • LRG_135:g.147276_147279del
  • NC_000011.9:g.108235832_108235835del
  • NC_000011.9:g.108235834_108235837del
  • NM_000051.3:c.8876_8879del
  • NM_000051.3:c.8876_8879delACTG
Protein change:
D2959fs
Links:
dbSNP: rs786204726
NCBI 1000 Genomes Browser:
rs786204726
Molecular consequence:
  • NM_000051.4:c.8876_8879del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001351834.2:c.8876_8879del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001330368.2:c.640+20812_640+20815del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.694+20812_694+20815del - intron variant - [Sequence Ontology: SO:0001627]
Observations:
2

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000581454Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Mar 14, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000903724Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 15, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001911492Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
criteria provided, single submitter

(Feliubadaló L et al. (Clin Chem 2021))
Pathogenic
(Jun 17, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
European caucasoidgermlineyes2not providednot provided2not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.

Mitui M, Campbell C, Coutinho G, Sun X, Lai CH, Thorstenson Y, Castellvi-Bel S, Fernandez L, Monros E, Carvalho BT, Porras O, Fontan G, Gatti RA.

Hum Mutat. 2003 Jul;22(1):43-50.

PubMed [citation]
PMID:
12815592
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000581454.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to 8879, causing a translational frameshift with a predicted alternate stop codon (p.D2959Gfs*3). This mutation has been previously identified in three individuals with ataxia telangiectasia, two of whom carried a second truncating ATM mutation (Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as 8874_8877delTGAC and 8875_8878delGACT 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV000903724.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant deletes 4 nucleotides in exon 62 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 3/251380 chromosomes 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 Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911492.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1European caucasoid1not providednot providedclinical testing PubMed (3)
2European caucasoid1not providednot providedclinical testing PubMed (3)

Description

Carrier of an heterozygous pathogenic variant in BRCA2

Description

The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/236,852 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0058%, (2/34,246 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been described in trans with the likely pathogenic ATM variant c.8977C>T in an ataxia-telangiectasia proband and in homozygosis in another, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3; PMID: 12815592, 27664052). Lymphoblastoid cell lines of the homozygous patient showed no ATM protein expression and intermediate radiosensitivity (PS3_Supporting; PMID: 27664052). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3 + PS3_Supporting (PMID: 33280026).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Feb 16, 2025