NM_007294.3(BRCA1):c.5468-2A>G AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Mar 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_007294.3(BRCA1):c.5468-2A>G]


BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000017.11:g.43045804T>C
  • NG_005905.2:g.172180A>G
  • NM_007294.3:c.5468-2A>G
  • NM_007297.4:c.5327-2A>G
  • NM_007298.3:c.2156-2A>G
  • NM_007299.4:c.2082-2A>G
  • NM_007300.4:c.5531-2A>G
  • LRG_292t1:c.5468-2A>G
  • LRG_292:g.172180A>G
  • NC_000017.10:g.41197821T>C
  • NM_007294.4:c.5468-2A>GMANE SELECT
Nucleotide change:
dbSNP: rs398122699
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_007294.3:c.5468-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007297.4:c.5327-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007298.3:c.2156-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007299.4:c.2082-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007300.4:c.5531-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
Functional consequence:
functionally_abnormal [Sequence Ontology: SO:0002218] - Comment(s)


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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001186114Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Mar 19, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

Golmard L, Delnatte C, Laugé A, Moncoutier V, Lefol C, Abidallah K, Tenreiro H, Copigny F, Giraudeau M, Guy C, Barbaroux C, Amorim G, Briaux A, Guibert V, Tarabeux J, Caputo S, Collet A, Gesta P, Ingster O, Stern MH, Rouleau E, de Pauw A, et al.

Oncogene. 2016 Mar 10;35(10):1324-7. doi: 10.1038/onc.2015.181. Epub 2015 Jun 1.

PubMed [citation]

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

Baert A, Machackova E, Coene I, Cremin C, Turner K, Portigal-Todd C, Asrat MJ, Nuk J, Mindlin A, Young S, MacMillan A, Van Maerken T, Trbusek M, McKinnon W, Wood ME, Foulkes WD, Santamariña M, de la Hoya M, Foretova L, Poppe B, Vral A, Rosseel T, et al.

Hum Mutat. 2018 Apr;39(4):515-526. doi: 10.1002/humu.23390. Epub 2018 Jan 22.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001186114.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)


The c.5468-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 22 in the BRCA1 gene. This alteration has been reported in multiple individuals from a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). It has also been reported as a de novo alteration in an individual with ovarian cancer at age 39, however it is it unclear if paternity was confirmed in this study (Golmard L et al. Oncogene, 2016 Mar;35:1324-7). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A close match alteration at this acceptor site, BRCA1 c.5468-1G>A was shown to make use of a cryptic acceptor site 11nt downstream (Baert A et al. Hum. Mutat., 2018 04;39:515-526). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic.

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

Last Updated: Sep 18, 2021

Support Center