NM_000051.4(ATM):c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jun 4, 2024
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:: RCV000579824.6

Allele description [Variation Report for NM_000051.4(ATM):c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA]

NM_000051.4(ATM):c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA

HGVS:

NC_000011.10:g.108294917_108294920delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
NG_009830.1:g.77086_77089delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
NM_000051.4:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAAMANE SELECT
NM_001351834.2:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
LRG_135t1:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
LRG_135:g.77086_77089delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
NC_000011.9:g.108165644_108165647delinsCTCTTTTAGTTACATTTACATTTTAGTTAA
NM_000051.3:c.4777-10_4777-7delTCTCinsCTCTTTTAGTTACATTTACATTTTAGTTAA
NM_000051.3:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA

Links:

dbSNP: rs1555101600

NCBI 1000 Genomes Browser:

rs1555101600

Molecular consequence:

NM_000051.4:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA - intron variant - [Sequence Ontology: SO:0001627]
NM_001351834.2:c.4777-10_4777-7delinsCTCTTTTAGTTACATTTACATTTTAGTTAA - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000682219	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005017347	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 26, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000682219

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 4, 2024)

germline

clinical testing

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

SCV005017347

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 26, 2023)

germline

clinical testing

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

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

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000682219.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant causes the deletion of 4 nucleotides and insertion of 30 nucleotides in intron 31/62 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar Accession: SCV005017347.1). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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, SCV005017347.1

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

Description

The c.4777-10_4777-7delTCTCins30 intronic variant begins 10 nucleotides before coding exon 31 in the ATM gene. This variant results from a deletion of 4 nucleotides and the insertion of 30 nucleotides at nucleotide positions c.4777-10 to c.4777-7. This nucleotide region is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: May 16, 2025

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