NM_000051.4(ATM):c.3372C>G (p.Tyr1124Ter) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic (Last evaluated: Aug 20, 2020)

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:
RCV000115176.10

Allele description [Variation Report for NM_000051.4(ATM):c.3372C>G (p.Tyr1124Ter)]

NM_000051.4(ATM):c.3372C>G (p.Tyr1124Ter)

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.3372C>G (p.Tyr1124Ter)
Other names:
p.Y1124*:TAC>TAG
HGVS:
  • NC_000011.10:g.108279578C>G
  • NG_009830.1:g.61747C>G
  • NM_000051.4:c.3372C>GMANE SELECT
  • NM_001351834.2:c.3372C>G
  • NP_000042.3:p.Tyr1124Ter
  • NP_000042.3:p.Tyr1124Ter
  • NP_001338763.1:p.Tyr1124Ter
  • LRG_135t1:c.3372C>G
  • LRG_135:g.61747C>G
  • LRG_135p1:p.Tyr1124Ter
  • NC_000011.9:g.108150305C>G
  • NM_000051.3:c.3372C>G
  • p.Tyr1124Stop
  • p.Y1124*
Protein change:
Y1124*
Links:
dbSNP: rs587779833
NCBI 1000 Genomes Browser:
rs587779833
Molecular consequence:
  • NM_000051.4:c.3372C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001351834.2:c.3372C>G - 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
SCV000186133Ambry Geneticscriteria provided, single submitter
Pathogenic
(Apr 24, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000911665Color Health, Inccriteria provided, single submitter
Pathogenic
(Aug 20, 2020)
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

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

Teraoka SN, Telatar M, Becker-Catania S, Liang T, Oneng├╝t S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P.

Am J Hum Genet. 1999 Jun;64(6):1617-31.

PubMed [citation]
PMID:
10330348
PMCID:
PMC1377904

Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.

Li A, Swift M.

Am J Med Genet. 2000 May 29;92(3):170-7.

PubMed [citation]
PMID:
10817650
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000186133.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.Y1124* pathogenic mutation (also known as c.3372C>G), located in coding exon 22 of the ATM gene, results from a C to G substitution at nucleotide position 3372. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation has been reported as both heterozygous and homozygous in ataxia-telangiectasia (A-T) patients to date (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7). This alteration has also been identified in an individual with breast cancer and pulmonary carcinoid (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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, SCV000911665.3

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

Description

This variant changes 1 nucleotide in exon 23 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 the homozygous and heterozygous state in individuals affected with ataxia telangiectasia (PMID: 10330348, 10817650). This variant has also been reported in an individual affected with breast and lung cancer (PMID: 26681312). This variant has been identified in 1/250920 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: Dec 4, 2021

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