NM_000051.4(ATM):c.7886_7890del (p.Ile2629fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 6, 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:: RCV000222650.19

Allele description [Variation Report for NM_000051.4(ATM):c.7886_7890del (p.Ile2629fs)]

NM_000051.4(ATM):c.7886_7890del (p.Ile2629fs)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.7886_7890del (p.Ile2629fs)

Other names:

7883del5

HGVS:

NC_000011.10:g.108332854TATTA[1]
NG_009830.1:g.115023TATTA[1]
NG_054724.1:g.141973TATAA[1]
NM_000051.4:c.7886_7890delMANE SELECT
NM_001330368.2:c.641-23784_641-23780del
NM_001351110.2:c.*38+2365_*38+2369del
NM_001351834.2:c.7886_7890del
NP_000042.3:p.Ile2629Serfs
NP_000042.3:p.Ile2629fs
NP_001338763.1:p.Ile2629fs
LRG_135t1:c.7881_7885TATTA[1]
LRG_135:g.115023TATTA[1]
LRG_135p1:p.Ile2629Serfs
NC_000011.9:g.108203578_108203582del
NC_000011.9:g.108203581TATTA[1]
NM_000051.3:c.7881_7885TATTA[1]
NM_000051.3:c.7883_7887delTTATA
NM_000051.3:c.7886_7890del
NM_000051.3:c.7886_7890del
NM_000051.3:c.7886_7890delTATTA
NP_000042.3:p.Ile2629SerfsTer25
c.7883_7887del5

Protein change:

I2629fs

Links:

OMIM: 607585.0015; dbSNP: rs1450394308

NCBI 1000 Genomes Browser:

rs1450394308

Molecular consequence:

NM_000051.4:c.7886_7890del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.7886_7890del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330368.2:c.641-23784_641-23780del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+2365_*38+2369del - 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
SCV000273655	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 26, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 21787400, 23322442, 23946315, 26436112, 29360550, 30287823, 34506673, 8845835 Citation Link,
SCV000682440	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 8845835, 9600235, 12815592, 21787400, 23322442, 23946315, 26436112, 30287823, 33471991, 34506673, 25741868
SCV002538260	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jun 25, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 8845835, 21787400, 23946315, 9711876, 26436112, 31050087 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000273655

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 26, 2021)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000682440

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 6, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002538260

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jun 25, 2021)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

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

Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations.

Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, Lawlor RT, Nakanishi Y, Mitsuhashi T, Fujimoto A, Furuta M, Ruzzenente A, Conci S, Oosawa A, Sasaki-Oku A, Nakano K, Tanaka H, Yamamoto Y, et al.

J Hepatol. 2018 May;68(5):959-969. doi: 10.1016/j.jhep.2018.01.009. Epub 2018 Jan 31.

PubMed [citation]

PMID:: 29360550

Mutations of the ATM gene detected in Japanese ataxia-telangiectasia patients: possible preponderance of the two founder mutations 4612del165 and 7883del5.

Ejima Y, Sasaki MS.

Hum Genet. 1998 Apr;102(4):403-8.

PubMed [citation]

PMID:: 9600235

See all PubMed Citations (14)

Details of each submission

From Ambry Genetics, SCV000273655.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The c.7886_7890delTATTA pathogenic mutation, located in coding exon 52 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 7886 to 7890, causing a translational frameshift with a predicted alternate stop codon (p.I2629Sfs*25). This pathogenic mutation has been reported in a family with two cases of breast cancer under age 50 and one individual with ataxia-telangiectasia (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This mutation has also been reported in a compound heterozygous state with another alteration in ATM [c.6154G>A (p.E2052K)] in an individual with cervical dopa-responsive dystonia (DRD) (Charlesworth G et al. Neurology. 2013 Sep;81:1148-51). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0002 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000682440.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant deletes 5 nucleotides in exon 53 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 (also known as 7883del5, 7884_7888del5, or c.7878_7882delTTATA in the literature) has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8845835, 9600235, 12815592, 23322442, 23946315). This variant has also been reported in individuals affected with breast cancer (PMID: 21787400, 26436112, 30287823, 33471991) or pancreatic ductal adenocarcinoma (PMID: 34506673). This variant has been identified in 1/250834 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.

#	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, SCV002538260.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

#	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 10, 2024

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