NM_000051.4(ATM):c.8833_8834del (p.Leu2945fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 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:: RCV000166157.16

Allele description [Variation Report for NM_000051.4(ATM):c.8833_8834del (p.Leu2945fs)]

NM_000051.4(ATM):c.8833_8834del (p.Leu2945fs)

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.8833_8834del (p.Leu2945fs)

HGVS:

NC_000011.10:g.108354855CT[1]
NG_009830.1:g.137024CT[1]
NG_054724.1:g.119975AG[1]
NM_000051.4:c.8833_8834delMANE SELECT
NM_001330368.2:c.640+31064_640+31065del
NM_001351110.2:c.695-19564_695-19563del
NM_001351834.2:c.8833_8834del
NP_000042.3:p.Leu2945Valfs
NP_000042.3:p.Leu2945fs
NP_001338763.1:p.Leu2945fs
LRG_135t1:c.8831_8832CT[1]
LRG_135:g.137024CT[1]
LRG_135p1:p.Leu2945Valfs
NC_000011.9:g.108225582CT[1]
NC_000011.9:g.108225582_108225583del
NM_000051.3:c.8831_8832CT[1]
NM_000051.3:c.8833_8834del
NM_000051.3:c.8833_8834del
NM_000051.3:c.8833_8834delCT
p.L2945VFS*10

Protein change:

L2945fs

Links:

dbSNP: rs786203030

NCBI 1000 Genomes Browser:

rs786203030

Molecular consequence:

NM_000051.4:c.8833_8834del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.8833_8834del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330368.2:c.640+31064_640+31065del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.695-19564_695-19563del - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000216930	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (May 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27599564, 29271107 Citation Link,
SCV000903221	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8659541, 10817650, 17124347, 19691550, 27599564, 29271107, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216930

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(May 2, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000903221

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 6, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Ataxia-telangiectasia: mutations in ATM cDNA detected by protein-truncation screening.

Telatar M, Wang Z, Udar N, Liang T, Bernatowska-Matuszkiewicz E, Lavin M, Shiloh Y, Concannon P, Good RA, Gatti RA.

Am J Hum Genet. 1996 Jul;59(1):40-4.

PubMed [citation]

PMID:: 8659541
PMCID:: PMC1915099

Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.

Li A, Swift M.

Am J Med Genet. 2000 May 29;92(3):170-7.

PubMed [citation]

PMID:: 10817650

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000216930.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The c.8833_8834delCT pathogenic mutation, located in coding exon 60 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 8833 to 8834, causing a translational frameshift with a predicted alternate stop codon (p.L2945Vfs*10). This mutation has been previously identified in multiple ataxia-telangiectasia patients (Telatar, M et al. Am J Hum Genet. 1996 Jul;59(1):40-4; Li, A & Swift, M. Am J Med Genet. 2000 May 29;92(3):170-7; Magliozzi, M et al. Dis Markers. 2006;22(4):257-64; Chessa, L et al. Ann Hum Genet. 2009 Sep;73(Pt 5):532-9). This alteration has also been identified in the heterozygous state in individuals diagnosed with breast cancer (Coppa A et al. Cancer Med. 2018 01;7:46-55; Prodosmo A et al. J. Exp. Clin. Cancer Res. 2016 09;35:135). 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000903221.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant deletes 2 nucleotides in exon 61 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 has been shown to segregate with breast cancer in three individuals from a family (PMID: 29271107) and has been reported in an individual affected with early-onset breast cancer (PMID: 27599564). In addition, this variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 8659541, 10817650, 17124347, 19691550). This variant has been identified in 1/251406 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

Last Updated: Apr 20, 2024

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