NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 26, 2024
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:: RCV000115219.22

Allele description [Variation Report for NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)]

NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)

Other names:

p.E1978*:GAA>TAA

HGVS:

NC_000011.10:g.108312424G>T
NG_009830.1:g.94593G>T
NG_054724.1:g.162409C>A
NM_000051.4:c.5932G>TMANE SELECT
NM_001330368.2:c.641-3353C>A
NM_001351110.2:c.*39-3353C>A
NM_001351834.2:c.5932G>T
NP_000042.3:p.Glu1978Ter
NP_000042.3:p.Glu1978Ter
NP_001338763.1:p.Glu1978Ter
LRG_135t1:c.5932G>T
LRG_135:g.94593G>T
LRG_135p1:p.Glu1978Ter
NC_000011.9:g.108183151G>T
NM_000051.3:c.5932G>T
p.E1978*
p.Glu1978Stop

Protein change:

E1978*

Links:

dbSNP: rs587779852

NCBI 1000 Genomes Browser:

rs587779852

Molecular consequence:

NM_001330368.2:c.641-3353C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-3353C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.5932G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.5932G>T - nonsense - [Sequence Ontology: SO:0001587]

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

Recent activity

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172771	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 10330348, 10817650, 10980530, 15880721, 16266405, 18807267, 19691550, 19781682, 25614872, 26380989, 26483394, 26506520, 27433846, 27449771, 28726808, 9443866, 9887333 Citation Link,
SCV000537636	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10330348, 15880721, 16266405, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000172771

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 26, 2024)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link,

SCV000537636

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 9, 2023)

germline

clinical testing

PubMed (4)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.

Laake K, Jansen L, Hahnemann JM, Brondum-Nielsen K, Lönnqvist T, Kääriäinen H, Sankila R, Lähdesmäki A, Hammarström L, Yuen J, Tretli S, Heiberg A, Olsen JH, Tucker M, Kleinerman R, Børresen-Dale AL.

Hum Mutat. 2000 Sep;16(3):232-46.

PubMed [citation]

PMID:: 10980530

See all PubMed Citations (18)

Details of each submission

From Ambry Genetics, SCV000172771.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide position 5932. This changes the amino acid from a glutamate to a stop codon within exon 40. This alteration has been reported in multiple individuals with ataxia-telangiectasia from various ethnic backgrounds and is likely a Russian founder mutation (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7; Birrell GW et al. Hum. Mutat. 2005 Jun;25(6):593; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11). In addition, p.E1978* has been described as a breast cancer susceptibility allele of Eastern European origin (Bogdanova N et al. Breast Cancer Res. Treat. 2009 Nov;118(1):207-11). It was also seen in a patient with prostate cancer with a Gleason score of 9 (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53) and in cohorts of pancreatic cancer patients (Chaffee KG et al. Genet Med. 2018 01;20:119-127; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). This mutation was shown to cause skipping of coding exon 39 (reported as exon 42), as well as a premature truncation in a subset of ATM transcripts (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by aberrant splicing, 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, SCV000537636.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant changes 1 nucleotide in exon 40 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has shown significant association with breast cancer in meta-analyses of multiple case-control studies (OR: 5.6, 95% CI: 1.3-21.4, p=0.01; PMID: 18807267) (OR: 4.56, 95% CI: 1.35-15.42, p=0.015; PMID: 21514219). This variant is a common cause of autosomal recessive ataxia-telangiectasia in Eastern Europe (PMID: 10330348, 15880721, 16266405). This variant has been identified in 11/251182 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: Nov 3, 2024

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