NM_000051.4(ATM):c.6096-9_6096-5del AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Oct 27, 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:: RCV001189626.15

Allele description [Variation Report for NM_000051.4(ATM):c.6096-9_6096-5del]

NM_000051.4(ATM):c.6096-9_6096-5del

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.6096-9_6096-5del

HGVS:

NC_000011.10:g.108316002_108316006del
NG_009830.1:g.98171_98175del
NG_054724.1:g.158831_158835del
NM_000051.4:c.6096-9_6096-5delMANE SELECT
NM_001330368.2:c.641-6931_641-6927del
NM_001351110.2:c.*39-6931_*39-6927del
NM_001351834.2:c.6096-9_6096-5del
LRG_135t1:c.6096-9_6096-5del
LRG_135:g.98171_98175del
NC_000011.9:g.108186725_108186729del
NC_000011.9:g.108186729_108186733del
NM_000051.3:c.6096-9_6096-5del
NM_000051.3:c.6096-9_6096-5del5
NM_000051.3:c.6096-9_6096-5delTTCTT

Links:

dbSNP: rs879254095

NCBI 1000 Genomes Browser:

rs879254095

Molecular consequence:

NM_000051.4:c.6096-9_6096-5del - intron variant - [Sequence Ontology: SO:0001627]
NM_001330368.2:c.641-6931_641-6927del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6931_*39-6927del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351834.2:c.6096-9_6096-5del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001356944	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537594	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Feb 12, 2022)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 9887333, 18497957, 1849795 Citation Link,
SCV002661021	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Oct 27, 2023)	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

SCV001356944

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 21, 2021)

germline

clinical testing

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

SCV002537594

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Feb 12, 2022)

germline

curation

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

Citation Link,

SCV002661021

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Oct 27, 2023)

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, curation

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

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D.

Hum Mol Genet. 1999 Jan;8(1):69-79.

PubMed [citation]

PMID:: 9887333

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001356944.2

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

Description

This variant deletes 5 nucleotides at the -9 to -5 position of intron 41 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that the variant leads to the skipping of exon 42 (also known as exon 44 in the literature) in the RNA transcript (PMID: 9887333, 18497957). The aberrant transcript is predicted to create a premature translation stop signal and is expected to result in an absent or non-functional protein product. This variant has been reported in the heterozygous state in an individual affected with ataxia telangiectasia (PMID: 9887333). This variant has also been reported in at least one individual affected with breast cancer (PMID: 18497957). This variant has been identified in 1/251274 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 Likely 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

From Sema4, Sema4, SCV002537594.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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, SCV002661021.2

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

Description

The c.6096-9_6096-5delTTCTT intronic variant is located 5 nucleotides upstream from coding exon 41 in the ATM gene. This variant results from a deletion of 5 nucleotides at positions c.6096-9 to c.6096-5. This alteration has been reported in a heterozygous state in an individual with ataxia telangiectasia (Sandoval N et al. Hum. Mol. Genet.1999 Jan;8(1):69-79). 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. Multiple RNA studies have shown that this alteration causes skipping of coding exon 41 (also designated as exon 44) (Sandoval N et al. Hum. Mol. Genet.1999 Jan;8(1):69-79; Soukupova J et al. Oncol. Rep., 2008 Jun;19:1505-10; 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: Nov 3, 2024

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