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NM_000059.4(BRCA2):c.9871del (p.Ser3291fs) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 30, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000776118.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.9871del (p.Ser3291fs)]

NM_000059.4(BRCA2):c.9871del (p.Ser3291fs)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.9871del (p.Ser3291fs)
Other names:
10099delT stop codon 3312
HGVS:
  • NC_000013.11:g.32398384del
  • NG_012772.3:g.87905del
  • NM_000059.4:c.9871delMANE SELECT
  • NP_000050.3:p.Ser3291fs
  • LRG_293:g.87905del
  • NC_000013.10:g.32972519del
  • NC_000013.10:g.32972521del
  • NM_000059.3:c.9871delT
  • NM_000059.4:c.9871del
  • p.Ser3291fs
Links:
dbSNP: rs886040854
NCBI 1000 Genomes Browser:
rs886040854
Molecular consequence:
  • NM_000059.4:c.9871del - frameshift variant - [Sequence Ontology: SO:0001589]

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000910992Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Aug 30, 2022) 		germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001181241Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Oct 15, 2019) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.

Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP.

Science. 2002 Sep 13;297(5588):1837-48.

PubMed [citation]
PMID:
12228710

Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats.

Davies OR, Pellegrini L.

Nat Struct Mol Biol. 2007 Jun;14(6):475-83. Erratum in: Nat Struct Mol Biol. 2007 Jul;14(7):680.

PubMed [citation]
PMID:
17515903
PMCID:
PMC2096194
See all PubMed Citations (10)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000910992.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This variant deletes 1 nucleotide in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is not expected to trigger nonsense-mediated decay. However, this truncation is expected to disrupt the TR2 region (a.a. 3265-3330) that mediates interaction with RAD51 protein important for homology-directed repair and related functions (PMID: 12228710, 17515903, 17515904, 25833843). C-terminal truncation, p.Tyr3308*, has been reported as disease-causing in ClinVar (variation ID: 52916, 267177) and shown to be defective in RAD51 foci formation, sensitivity to DNA damaging agents, and chromosomal aberration assays in complementation of human and mouse BRCA2-deficient cells (PMID: 18593900, 18607349, 33293522). This variant has been reported in a family affected with pancreatic cancer and breast or ovarian cancer (PMID: 30736435). 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 Pathogenic.

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

From Ambry Genetics, SCV001181241.4

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

Description

The c.9871delT pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9871, causing a translational frameshift with a predicted alternate stop codon (p.S3291Lfs*22). 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 alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Nov 3, 2024