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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MAG: Gemmatimonadetes bacterium 13_1_20CM_69_28 13_1_20cm_full_scaffold_479, who...
MAG: Gemmatimonadetes bacterium 13_1_20CM_69_28 13_1_20cm_full_scaffold_479, whole genome shotgun sequence
gi|1125431594|gb|MNIC01000006.1||gn :MNIC01|13_1_20cm_full_scaffold_479

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000687406	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 31, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12552559, 26896183, 25741868
SCV002739690	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 25, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000687406

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 31, 2023)

germline

clinical testing

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

SCV002739690

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 25, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002739690.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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