NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Jan 4, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000129649.9

Allele description [Variation Report for NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter)]

NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter)

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.7913G>A (p.Trp2638Ter)
Other names:
p.W2638*:TGG>TAG
HGVS:
  • NC_000011.10:g.108332886G>A
  • NG_009830.1:g.115055G>A
  • NG_054724.1:g.141947C>T
  • NM_000051.3:c.7913G>A
  • NM_000051.4:c.7913G>AMANE SELECT
  • NM_001330368.2:c.641-23815C>T
  • NM_001351110.2:c.*38+2334C>T
  • NM_001351834.2:c.7913G>A
  • NP_000042.3:p.Trp2638Ter
  • NP_000042.3:p.Trp2638Ter
  • NP_001338763.1:p.Trp2638Ter
  • LRG_135t1:c.7913G>A
  • LRG_135:g.115055G>A
  • LRG_135p1:p.Trp2638Ter
  • NC_000011.9:g.108203613G>A
  • NC_000011.9:g.108203613G>A
  • p.W2638*
Protein change:
W2638*
Links:
dbSNP: rs377349459
NCBI 1000 Genomes Browser:
rs377349459
Molecular consequence:
  • NM_001330368.2:c.641-23815C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.*38+2334C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.3:c.7913G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000051.4:c.7913G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001351834.2:c.7913G>A - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000184447Ambry Geneticscriteria provided, single submitter
Pathogenic
(Jun 1, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000687802Color Health, Inccriteria provided, single submitter
Pathogenic
(Jan 4, 2021)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.

Mitui M, Campbell C, Coutinho G, Sun X, Lai CH, Thorstenson Y, Castellvi-Bel S, Fernandez L, Monros E, Carvalho BT, Porras O, Fontan G, Gatti RA.

Hum Mutat. 2003 Jul;22(1):43-50.

PubMed [citation]
PMID:
12815592

Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations.

Coutinho G, Mitui M, Campbell C, Costa Carvalho BT, Nahas S, Sun X, Huo Y, Lai CH, Thorstenson Y, Tanouye R, Raskin S, Kim CA, Llerena J Jr, Gatti RA.

Am J Med Genet A. 2004 Apr 1;126A(1):33-40.

PubMed [citation]
PMID:
15039971
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000184447.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.W2638* pathogenic mutation (also known as c.7913G>A), located in coding exon 52 of the ATM gene, results from a G to A substitution at nucleotide position 7913. This changes the amino acid from a tryptophan to a stop codon within coding exon 52. This mutation has been reported in a compound heterozygous or homozygous state in multiple individuals with classic ataxia-telangiectasia (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Coutinho G et al. Am. J. Med. Genet. A. 2004 Apr;126A:33-40​; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82). This mutation was also detected in 1/692 men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). In addition to the clinical data presented in the literature, 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000687802.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant changes 1 nucleotide in exon 53 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with male breast cancer and prostate, liver, colon cancer and melanoma (PMID: 26681312, 27433846, 28008555), and in homozygous and compound heterozygous carriers affected with ataxia-telangiectasia (PMID: 9711876, 15039971, 21965147). Haplotype analyses suggest this variant may be a founder mutation in individuals of African ancestry (PMID: 12815592, 15039971). This variant has been identified in 5/281730 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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