NM_000051.4(ATM):c.8786+1G>T AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 17, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:

Allele description [Variation Report for NM_000051.4(ATM):c.8786+1G>T]


ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000011.10:g.108353881G>T
  • NG_009830.1:g.136050G>T
  • NG_054724.1:g.120952C>A
  • NM_000051.3:c.8786+1G>T
  • NM_000051.4:c.8786+1G>TMANE SELECT
  • NM_001330368.2:c.640+32039C>A
  • NM_001351110.2:c.695-18589C>A
  • NM_001351834.2:c.8786+1G>T
  • LRG_135t1:c.8786+1G>T
  • LRG_135:g.136050G>T
  • NC_000011.9:g.108224608G>T
  • NC_000011.9:g.108224608G>T
dbSNP: rs17174393
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001330368.2:c.640+32039C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.695-18589C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.3:c.8786+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_000051.4:c.8786+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351834.2:c.8786+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]


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)
SCV000214657Ambry Geneticscriteria provided, single submitter
(Nov 15, 2019)
germlineclinical testing

Citation Link,

SCV001353288Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Nov 26, 2019)
germlineclinical testing

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

SCV001911491Spanish ATM Cancer Susceptibility Variant Interpretation Working Groupcriteria provided, single submitter
(Jun 17, 2020)
germlineclinical testing

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


This variant causes a G>T nucleotide substitution at the +1 position of intron 60 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. 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. Based on the available evidence, this variant is classified as Likely Pathogenic.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing
European caucasoidgermlineyes1not providednot provided1not providedclinical testing



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]

A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.

Feliubadaló L, Moles-Fernández A, Santamariña-Pena M, Sánchez AT, López-Novo A, Porras LM, Blanco A, Capellá G, de la Hoya M, Molina IJ, Osorio A, Pineda M, Rueda D, de la Cruz X, Diez O, Ruiz-Ponte C, Gutiérrez-Enríquez S, Vega A, Lázaro C.

Clin Chem. 2021 Mar 1;67(3):518-533. doi: 10.1093/clinchem/hvaa250.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000214657.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.8786+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 59 of the ATM gene. To our knowledge, this alteration has not been reported in published literature to date; however, a different nucleotide change at the same position, c.8786+1G>A (also known as IVS62+1G>A), has been detected in numerous ataxia-telangiectasia kindreds (Stankovic T et al. Am J Hum Genet. 1998 Feb;62(2):334-45; Laake K et al. Hum Mutat. 2000 Sep;16(3):232-46; Li A and Swift M. Am J Med Genet. 2000 May 29;92(3):170-7). Based on two different splice site prediction tools, the c.8786+1G>T alteration is expected to abolish 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

From Color Health, Inc, SCV001353288.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911491.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1European caucasoid1not providednot providedclinical testing PubMed (1)


The c.8786+1G>T variant is located in the canonical donor splice site of intron 60 and it is predicted to cause the skipping of exon 60 and the disruption of the reading frame, and to undergo nonsense mediated decay (NMD) (PVS1). It is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). Semiquantitative splicing analysis shows a 55% of altered band and 45% of wild type band after RT-PCR of puromycin-cultured lymphocyte carrier RNA. The altered band is the result of the predicted skipping of exon 60 (PS3_Moderate; M. Santamariña and A. Vega., unpublished data). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM2 + PS3_Moderate (PMID: 33280026).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Nov 20, 2021

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