NM_000051.4(ATM):c.3078-1G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 30, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000051.4(ATM):c.3078-1G>A]


ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000011.10:g.108272531G>A
  • NG_009830.1:g.54700G>A
  • NM_000051.4:c.3078-1G>AMANE SELECT
  • NM_001351834.2:c.3078-1G>A
  • LRG_135t1:c.3078-1G>A
  • LRG_135:g.54700G>A
  • NC_000011.9:g.108143258G>A
  • NM_000051.3:c.3078-1G>A
dbSNP: rs750663117
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000051.4:c.3078-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001351834.2:c.3078-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000275071Ambry Geneticscriteria provided, single submitter
(Jul 30, 2020)
germlineclinical testing

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

Citation Link,

SCV000687450Color Health, Inccriteria provided, single submitter
Likely pathogenic
(May 18, 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



Rapid and efficient ATM mutation detection by fluorescent chemical cleavage of mismatch: identification of four novel mutations.

Izatt L, Vessey C, Hodgson SV, Solomon E.

Eur J Hum Genet. 1999 Apr;7(3):310-20.

PubMed [citation]

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]

Details of each submission

From Ambry Genetics, SCV000275071.6

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


The c.3078-1G>A intronic pathogenic mutation results from a G to A one nucleotide upstream from coding exon 20 of the ATM gene. This mutation has been reported in a compound heterozygote state in a 5 year old male with classic Ataxia telangiectasia. In addition, sequencing of cDNA for this individual identified coding exon 20 skipping, deleting 76 bp, resulting in a frameshift (Izatt L et al, Eur. J. Hum. Genet. 1999 Apr; 7(3):310-20). 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 abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

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

From Color Health, Inc, SCV000687450.4

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


This variant causes a G to A nucleotide substitution at the -1 position of intron 20 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant causes skipping of the subsequent exon 21 (PMID: 10234507). This variant has been reported in one individual affected with Ataxia-telangiectasia in compound heterozygous state with another pathogenic ATM co-variant (PMID: 10234507). This variant has been identified in 2/251084 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 Likely Pathogenic.

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

Last Updated: Nov 27, 2021

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