NM_000051.4(ATM):c.2377-2A>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 29, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000568118.8

Allele description [Variation Report for NM_000051.4(ATM):c.2377-2A>G]

NM_000051.4(ATM):c.2377-2A>G

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.2377-2A>G

HGVS:

NC_000011.10:g.108258984A>G
NG_009830.1:g.41153A>G
NM_000051.4:c.2377-2A>GMANE SELECT
NM_001351834.2:c.2377-2A>G
LRG_135t1:c.2377-2A>G
LRG_135:g.41153A>G
NC_000011.9:g.108129711A>G
NM_000051.3:c.2377-2A>G

Links:

dbSNP: rs1057516553

NCBI 1000 Genomes Browser:

rs1057516553

Molecular consequence:

NM_000051.4:c.2377-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001351834.2:c.2377-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase [Homo sapiens]
tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase [Homo sapiens]
gi|4507613|ref|NP_003738.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000660467	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 29, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27039262, 30982232 Citation Link,
SCV000910309	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 18, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000660467

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 29, 2021)

germline

clinical testing

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

Citation Link,

SCV000910309

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 18, 2020)

germline

clinical testing

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

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

Identification of Gene Mutations and Fusion Genes in Patients with Sézary Syndrome.

Prasad A, Rabionet R, Espinet B, Zapata L, Puiggros A, Melero C, Puig A, Sarria-Trujillo Y, Ossowski S, Garcia-Muret MP, Estrach T, Servitje O, Lopez-Lerma I, Gallardo F, Pujol RM, Estivill X.

J Invest Dermatol. 2016 Jul;136(7):1490-1499. doi: 10.1016/j.jid.2016.03.024. Epub 2016 Mar 30.

PubMed [citation]

PMID:: 27039262

Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes.

Wang J, Li W, Shi Y, Huang Y, Sun T, Tang L, Lu Q, Lei Q, Liao N, Jin F, Li H, Huang T, Qian J, Pang D, Wang S, Fan P, Wu X, Lin Y, Qin H, Xu B.

Cancer Med. 2019 May;8(5):2074-2084. doi: 10.1002/cam4.2093. Epub 2019 Apr 13.

PubMed [citation]

PMID:: 30982232
PMCID:: PMC6536923

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000660467.5

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

Description

The c.2377-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the ATM gene. This alteration was detected in 1/15 patients with Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course (Prasad A et al. J. Invest. Dermatol., 2016 Jul;136:1490-9). It has also been detected in at least one individual from a cohort of 481 Chinese patients with a personal and or family history of breast cancer (Wang J et al. Cancer Med, 2019 05;8:2074-2084). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion deletion of one amino acid(s); however, the exact functional impact of the deleted amino acid is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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, SCV000910309.2

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

Description

This variant causes an A to G nucleotide substitution at the -2 position of intron 15 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Se'zary Syndrome, a leukemic form of cutaneous T-cell lymphoma (PMID: 27039262). 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 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

Last Updated: Sep 29, 2024

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