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NM_000051.4(ATM):c.2639-22_2639-20del AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 31, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000583624.14

Allele description [Variation Report for NM_000051.4(ATM):c.2639-22_2639-20del]

NM_000051.4(ATM):c.2639-22_2639-20del

Gene:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.2639-22_2639-20del
HGVS:
  • NC_000011.10:g.108268388_108268390del
  • NG_009830.1:g.50557_50559del
  • NM_000051.4:c.2639-22_2639-20delMANE SELECT
  • NM_001351834.2:c.2639-22_2639-20del
  • LRG_135:g.50557_50559del
  • NC_000011.9:g.108139114_108139116del
  • NC_000011.9:g.108139115_108139117del
  • NM_000051.3:c.2639-22_2639-20delAAT
Links:
dbSNP: rs1064795554
NCBI 1000 Genomes Browser:
rs1064795554
Molecular consequence:
  • NM_000051.4:c.2639-22_2639-20del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351834.2:c.2639-22_2639-20del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000687406Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jan 31, 2023)
germlineclinical testing

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

SCV002739690Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Aug 25, 2021)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Comprehensive scanning of the ATM gene with DOVAM-S.

Buzin CH, Gatti RA, Nguyen VQ, Wen CY, Mitui M, Sanal O, Chen JS, Nozari G, Mengos A, Li X, Fujimura F, Sommer SS.

Hum Mutat. 2003 Feb;21(2):123-31.

PubMed [citation]
PMID:
12552559

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
See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000687406.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This variant causes a 3-nucleotide deletion in the intron 17 splice acceptor site at a predicted branchpoint of the ATM gene. Splicing prediction algorithms have contradictory predictions for the splicing impact. A RNA study has reported that this variant caused abnormal RNA splicing (ClinVar RCV000583624.4). This variant has been reported in two individuals affected with ataxia telangiectasia with the same ATM co-variant c.5177+1G>C (PMID: 26896183) and as a heterozygous mutation in a family affected with ataxia telangiectasia with no other reported pathogenic mutation (PMID: 12552559). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From Ambry Genetics, SCV002739690.2

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

Description

The c.2639-22_2639-20delAAT pathogenic mutation, located in intron 16 of the ATM gene, results from a deletion of 3 nucleotides within intron 16 of the ATM gene. This variant was identified in conjunction with a likely pathogenic variant in ATM in one individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). These nucleotide positions are well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Oct 8, 2024