NM_007294.3(BRCA1):c.4357+6T>C AND Hereditary breast and ovarian cancer syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 15, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_007294.3(BRCA1):c.4357+6T>C]


BRCA1:BRCA1 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000017.11:g.43082398A>G
  • NG_005905.2:g.135586T>C
  • NM_007294.3:c.4357+6T>C
  • NM_007297.4:c.4216+6T>C
  • NM_007298.3:c.1048+6T>C
  • NM_007299.4:c.1048+6T>C
  • NM_007300.4:c.4357+6T>C
  • LRG_292t1:c.4357+6T>C
  • LRG_292:g.135586T>C
  • NC_000017.10:g.41234415A>G
  • NM_007294.4:c.4357+6T>CMANE SELECT
  • U14680.1:n.4476+6T>C
Nucleotide change:
Breast Cancer Information Core (BIC) (BRCA1): 4476+6&base_change=T to C; dbSNP: rs80358143
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_007294.3:c.4357+6T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007297.4:c.4216+6T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007298.3:c.1048+6T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007299.4:c.1048+6T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_007300.4:c.4357+6T>C - intron variant - [Sequence Ontology: SO:0001627]


Hereditary breast and ovarian cancer syndrome (HBOC)
Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC)
MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145; OMIM: PS604370

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000897863Cancer Variant Interpretation Group UK, Institute of Cancer Research, Londoncriteria provided, single submitter
(Oct 31, 2018)
germlineclinical testing

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

SCV001496382Invitaecriteria provided, single submitter
Uncertain significance
(Sep 15, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes19not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot 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]

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, Love R, Evans G, Easton D, Clayton D, Stratton MR, Ponder BA.

Nat Genet. 1995 Dec;11(4):428-33.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV000897863.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided19not providednot providedclinical testing PubMed (1)


Data used in classification: The variant was observed in 8 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (8/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 3e-06). At least 11 additional families have been identified in the UK (source DMuDB, these are not included in the previous dataset).There are additional reports of this variant on ClinVar. In the remainder of the GNOMAD populations (75,263 individuals), the frequency of this variant is 0. mRNA analysis of 2 patient samples and 5 controls was performed in a UK diagnostic laboratory on puromycin treated short term PHA stimulated lymphocyte cultures which showed that approx. 42.5% of the total RNA product was abnormally spliced excluding the whole of BRCA1 exon 12 resulting in disruption of the reading frame with incorporation of premature STOP codon at the start of BRAC1 exon 13. Skipping of exon13 (172 bases; out of frame) is also reported in Walker et al. Human Mutation 2013 and Gayther et al 1995 Nat Genet. PMID:7493024.. Additional data (not used in classification): Of note, insilico predictions of splicing effect for this variant were not strong (% change MaxEnt Score: -5.05, % change NNS Score: -6.95). The four UK families for whom pedigree data were available had a strong pattern of HBOC (Manchester score 20, 31, 25, 33). Additional samples from affected individual were not available for segregation analyses.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided19not providednot providednot provided

From Invitae, SCV001496382.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


This sequence change falls in intron 12 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 7493024, 29446198, 30586678). This variant is also known as 4476+6T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37585). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30586678). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 18, 2021

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