U.S. flag

An official website of the United States government

NM_000059.4(BRCA2):c.475+3A>G AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 5, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000772645.13

Allele description [Variation Report for NM_000059.4(BRCA2):c.475+3A>G]

NM_000059.4(BRCA2):c.475+3A>G

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.475+3A>G
HGVS:
  • NC_000013.11:g.32326153A>G
  • NG_012772.3:g.15674A>G
  • NM_000059.4:c.475+3A>GMANE SELECT
  • LRG_293t1:c.475+3A>G
  • LRG_293:g.15674A>G
  • NC_000013.10:g.32900290A>G
  • NM_000059.3:c.475+3A>G
Links:
dbSNP: rs81002795
NCBI 1000 Genomes Browser:
rs81002795
Molecular consequence:
  • NM_000059.4:c.475+3A>G - intron variant - [Sequence Ontology: SO:0001627]
Functional consequence:
effect on RNA splicing [Variation Ontology: 0362]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000905897Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Feb 4, 2020) 		germlineclinical testing

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

SCV005027324Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Oct 5, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

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]
PMID:
25741868
PMCID:
PMC4544753

Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.

Tea MK, Kroiss R, Muhr D, Fuerhauser-Rappaport C, Oefner P, Wagner TM, Singer CF.

Maturitas. 2014 Jan;77(1):68-72. doi: 10.1016/j.maturitas.2013.09.012. Epub 2013 Oct 1.

PubMed [citation]
PMID:
24156927
See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000905897.3

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

Description

This variant causes an A to G nucleotide substitution at the +3 position of intron 5 in the BRCA2 gene. Analysis of carrier RNA found the skipping of exon 5 that is predicted to create a premature translation termination and is expected to produce an absent or non-functional protein product (PMID: 9971877, 28905878). This variant has been observed in at least three individuals affected with breast cancer (Color Internal database and an external clinical laboratory) and an individual affected with breast and/or ovarian cancer (PMID: 28905878, Universal Mutation Database). This variant also has been reported in a family affected with three cases of breast cancer and one member with breast and ovarian cancer (PMID: 9971877, 24156927). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

From Ambry Genetics, SCV005027324.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The c.475+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 4 in the BRCA2 gene. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620), and was also reported in another cohort of individuals with a personal or family history of breast and/or ovarian cancer (Tea MK et al. Maturitas, 2014 Jan;77:68-72). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. One study reported that this alteration was associated with abnormal splicing (skipping of exon 5, Davy G et al. Eur J Hum Genet, 2017 Oct;25:1147-1154). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

Last Updated: Oct 8, 2024