NM_000051.4(ATM):c.5697C>A (p.Cys1899Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 25, 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:: RCV002350067.4

Allele description [Variation Report for NM_000051.4(ATM):c.5697C>A (p.Cys1899Ter)]

NM_000051.4(ATM):c.5697C>A (p.Cys1899Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.5697C>A (p.Cys1899Ter)

HGVS:

NC_000011.10:g.108307919C>A
NG_009830.1:g.90088C>A
NG_054724.1:g.166914G>T
NM_000051.4:c.5697C>AMANE SELECT
NM_001351834.2:c.5697C>A
NP_000042.3:p.Cys1899Ter
NP_000042.3:p.Cys1899Ter
NP_001338763.1:p.Cys1899Ter
LRG_135t1:c.5697C>A
LRG_135:g.90088C>A
LRG_135p1:p.Cys1899Ter
NC_000011.9:g.108178646C>A
NM_000051.3:c.5697C>A

Protein change:

C1899*

Links:

dbSNP: rs753839301

NCBI 1000 Genomes Browser:

rs753839301

Molecular consequence:

NM_000051.4:c.5697C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.5697C>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002653389	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 25, 2023)	germline	clinical testing	Citation Link,
SCV004361763	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23726790, 31788995, 33471991, 33919281, 34247626, 34659905, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002653389

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 25, 2023)

germline

clinical testing

Citation Link,

SCV004361763

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 18, 2022)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders.

Chen Z, Wang JL, Tang BS, Sun ZF, Shi YT, Shen L, Lei LF, Wei XM, Xiao JJ, Hu ZM, Pan Q, Xia K, Zhang QY, Dai MZ, Liu Y, Ashizawa T, Jiang H.

Neurobiol Aging. 2013 Oct;34(10):2442.e11-7. doi: 10.1016/j.neurobiolaging.2013.04.029. Epub 2013 May 30.

PubMed [citation]

PMID:: 23726790

Maintenance of pegylated liposomal doxorubicin/carboplatin in patients with advanced ovarian cancer: randomized study of an Asian Gynecologic Oncology Group.

Lai CH, Vallikad E, Lin H, Yang LY, Jung SM, Liu HE, Ou YC, Chou HH, Lin CT, Huang HJ, Huang KG, Qiu J, Hung YC, Wu TI, Chang WY, Tan KT, Lin CY, Chao A, Chang CJ.

J Gynecol Oncol. 2020 Jan;31(1):e5. doi: 10.3802/jgo.2020.31.e5. Epub 2019 Jul 26.

PubMed [citation]

PMID:: 31788995
PMCID:: PMC6918895

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002653389.3

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

Description

The p.C1899* pathogenic mutation (also known as c.5697C>A), located in coding exon 37 of the ATM gene, results from a C to A substitution at nucleotide position 5697. This changes the amino acid from a cysteine to a stop codon within coding exon 37. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, SCV004361763.1

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

Description

This variant changes 1 nucleotide in exon 38 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 been reported in individuals affected with ovarian cancer, breast cancer, pancreatic cancer (including pancreatic ductal adenocarcinoma), and colon cancer (PMID: 31788995, 33471991, 33919281, 34247626, 34659905; DOI: 10.1158/1538-7445.AM2021-805). This variant has also been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (PMID: 23726790) and in trans with an ATM variant of uncertain significance in an individual affected with cervical dystonia and cerebellar ataxia who also carried two SYNE1 variants in trans (DOI: 10.21203/rs.3.rs-577033/v1). This variant has not been identified 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: Sep 29, 2024

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