U.S. flag

An official website of the United States government

NM_000059.4(BRCA2):c.516+1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 21, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002338818.10

Allele description [Variation Report for NM_000059.4(BRCA2):c.516+1G>T]

NM_000059.4(BRCA2):c.516+1G>T

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.516+1G>T
HGVS:
  • NC_000013.11:g.32326283G>T
  • NG_012772.3:g.15804G>T
  • NM_000059.4:c.516+1G>TMANE SELECT
  • NM_001406719.1:c.516+1G>T
  • NM_001406720.1:c.516+1G>T
  • NM_001406721.1:c.516+1G>T
  • NM_001406722.1:c.147+1G>T
  • LRG_293t1:c.516+1G>T
  • LRG_293:g.15804G>T
  • NC_000013.10:g.32900420G>T
  • NM_000059.3:c.516+1G>T
Links:
dbSNP: rs397507762
NCBI 1000 Genomes Browser:
rs397507762
Molecular consequence:
  • NM_000059.4:c.516+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406719.1:c.516+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406720.1:c.516+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406721.1:c.516+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001406722.1:c.147+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002641351Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(May 21, 2024) 		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

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, et al.

Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

PubMed [citation]
PMID:
29446198
PMCID:
PMC5903938

Mis-splicing in breast cancer: identification of pathogenic BRCA2 variants by systematic minigene assays.

Fraile-Bethencourt E, Valenzuela-Palomo A, Díez-Gómez B, Goina E, Acedo A, Buratti E, Velasco EA.

J Pathol. 2019 Aug;248(4):409-420. doi: 10.1002/path.5268. Epub 2019 Apr 23.

PubMed [citation]
PMID:
30883759
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002641351.3

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

Description

The c.516+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 5 of the BRCA2 gene. 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. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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. RNA studies have demonstrated that this alteration results in abnormal splicing (Ambry internal data; Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420; Mesman RLS et al. Genet Med, 2020 08;22:1355-1365). In addition, this alteration was unable to complement cell growth in a BRCA2-null mouse embryonic stem cell assay (Mesman RLS et al. Genet Med, 2020 08;22:1355-1365). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Oct 26, 2024