NM_000051.4(ATM):c.8268+1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 14, 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:: RCV000220293.13

Allele description [Variation Report for NM_000051.4(ATM):c.8268+1G>T]

NM_000051.4(ATM):c.8268+1G>T

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.8268+1G>T

HGVS:

NC_000011.10:g.108335962G>T
NG_009830.1:g.118131G>T
NG_054724.1:g.138871C>A
NM_000051.4:c.8268+1G>TMANE SELECT
NM_001330368.2:c.641-26891C>A
NM_001351110.2:c.695-670C>A
NM_001351834.2:c.8268+1G>T
LRG_135t1:c.8268+1G>T
LRG_135:g.118131G>T
NC_000011.9:g.108206689G>T
NM_000051.3:c.8268+1G>T

Links:

dbSNP: rs876658957

NCBI 1000 Genomes Browser:

rs876658957

Molecular consequence:

NM_001330368.2:c.641-26891C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.695-670C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8268+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001351834.2:c.8268+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000274842	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Jun 14, 2023)	germline	clinical testing	Citation Link,
SCV001734900	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 28, 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

SCV000274842

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely pathogenic
(Jun 14, 2023)

germline

clinical testing

Citation Link,

SCV001734900

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 28, 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000274842.7

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

Description

The c.8268+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 55 of the ATM gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be 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 Color Diagnostics, LLC DBA Color Health, SCV001734900.1

#	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 a G>T nucleotide substitution at the +1 position of intron 56 splice donor site of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, this variant is predicted to cause an in-frame deletion of exon 56 that encodes a part of the kinase domain. A Likely Pathogenic missense variant has been reported in this exon (Clinvar variation ID: 646274), suggesting that exon 56 is important for ATM function and this splice variant is likely to impair ATM protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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: Apr 15, 2024

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