NM_000051.4(ATM):c.7088del (p.Lys2363fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 31, 2022
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:: RCV000216898.15

Allele description [Variation Report for NM_000051.4(ATM):c.7088del (p.Lys2363fs)]

NM_000051.4(ATM):c.7088del (p.Lys2363fs)

Genes:

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

Variant type:

Deletion

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.7088del (p.Lys2363fs)

HGVS:

NC_000011.10:g.108327757del
NG_009830.1:g.109926del
NG_054724.1:g.147079del
NM_000051.4:c.7088delMANE SELECT
NM_001330368.2:c.641-18683del
NM_001351110.2:c.*38+7466del
NM_001351834.2:c.7088del
NP_000042.3:p.Lys2363Argfs
NP_000042.3:p.Lys2363fs
NP_001338763.1:p.Lys2363fs
LRG_135t1:c.7088del
LRG_135:g.109926del
NC_000011.10:g.108327757delA
NC_000011.9:g.108198481del
NC_000011.9:g.108198484del
NM_000051.3:c.7088del
NM_000051.3:c.7088delA

Protein change:

K2363fs

Links:

dbSNP: rs876658512

NCBI 1000 Genomes Browser:

rs876658512

Molecular consequence:

NM_000051.4:c.7088del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.7088del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330368.2:c.641-18683del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+7466del - intron variant - [Sequence Ontology: SO:0001627]

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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Mus musculus RIKEN cDNA 1700029F09 gene, mRNA (cDNA clone MGC:155348 IMAGE:87337...
Mus musculus RIKEN cDNA 1700029F09 gene, mRNA (cDNA clone MGC:155348 IMAGE:8733781), complete cds
gi|111601047|gb|BC119032.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000273859	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 31, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001357927	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 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

SCV000273859

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 31, 2022)

germline

clinical testing

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

Citation Link,

SCV001357927

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 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

Two Novel Mutations Associated With Ataxia-Telangiectasia Identified Using an Ion AmpliSeq Inherited Disease Panel.

Kuznetsova MV, Trofimov DY, Shubina ES, Kochetkova TO, Karetnikova NA, Barkov IY, Bakharev VA, Gusev OA, Sukhikh GT.

Front Neurol. 2017;8:570. doi: 10.3389/fneur.2017.00570.

PubMed [citation]

PMID:: 29163336
PMCID:: PMC5670107

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, SCV000273859.7

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

Description

The c.7088delA pathogenic mutation, located in coding exon 47 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 7088, causing a translational frameshift with a predicted alternate stop codon (p.K2363Rfs*3). This alteration was identified in the homozygous state in two siblings with ataxia-telangiectasia (Kuznetsova MV et al. Front Neurol. 2017 Oct;8:570). 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, SCV001357927.2

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

Description

This variant deletes 1 nucleotide in exon 48 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 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: Nov 10, 2024

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