NM_007294.4(BRCA1):c.4485-2A>G AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 12, 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_007294.4(BRCA1):c.4485-2A>G]


BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000017.11:g.43074523T>C
  • NG_005905.2:g.143461A>G
  • NM_007294.3:c.4485-2A>G
  • NM_007294.4:c.4485-2A>GMANE SELECT
  • NM_007297.4:c.4344-2A>G
  • NM_007298.3:c.1173-2A>G
  • NM_007299.4:c.1173-2A>G
  • NM_007300.4:c.4548-2A>G
  • LRG_292t1:c.4485-2A>G
  • LRG_292:g.143461A>G
  • NC_000017.10:g.41226540T>C
  • U14680.1:n.4604-2A>G
Nucleotide change:
Breast Cancer Information Core (BIC) (BRCA1): 4604-2&base_change=A to G; dbSNP: rs80358054
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_007294.3:c.4485-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007294.4:c.4485-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007297.4:c.4344-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007298.3:c.1173-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007299.4:c.1173-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007300.4:c.4548-2A>G - 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)
SCV000186940Ambry Geneticscriteria provided, single submitter
(Jun 12, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000909024Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Apr 23, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod



Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population.

Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, Fujii T, Nagata I, Ushijima K, Obata K, Suzuki M, Yoshinaga M, Umesaki N, Satoh S, Enomoto T, Motoyama S, Tanaka K; Japanese Familial Ovarian Cancer Study Group..

Clin Cancer Res. 2001 Oct;7(10):3144-50.

PubMed [citation]

Sensitivity of BRCA1/2 mutation testing in 466 breast/ovarian cancer families.

Evans DG, Bulman M, Young K, Gokhale D, Lalloo F.

J Med Genet. 2003 Sep;40(9):e107. No abstract available.

PubMed [citation]
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000186940.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (7)


The c.4485-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 13 in the BRCA1 gene. Also designated as IVS14-2A>G and 4604-2A>G in published literature, this alteration has been reported in several families with breast and/or ovarian cancers (Shattuck-Eidens D et al. JAMA. 1997 Oct 15;278(15):1242-50; Sekine M et al. Clin Cancer Res. 2001 Oct;7(10):3144-50; Evans DG et al. J Med Genet. 2003 Sep;40(9):e107; Nakamura S et al. Breast Cancer<span style="color:rgb(54, 43, 54); font-family:arial"> 2015 Sep;22(5):462-8). This alteration has also been reported with a carrier frequency of 1 in 7051 unselected breast cancer patients and 0 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In vivo studies conducted in an EOC cell line homozygous for a different alteration at this splice acceptor site, c.4485-1G>T, identified the presence of a novel transcript induced by abnormal splicing, resulting in the absence of BRCA1 protein (Fleury H et al. Genes Cancer, 2015 Sep;6:378-398). In addition to the clinical data presented in the literature, 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. 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, SCV000909024.2

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

Last Updated: Jun 14, 2021

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