NM_000059.4(BRCA2):c.7876T>C (p.Trp2626Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 12, 2020
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:: RCV001026898.4

Allele description [Variation Report for NM_000059.4(BRCA2):c.7876T>C (p.Trp2626Arg)]

NM_000059.4(BRCA2):c.7876T>C (p.Trp2626Arg)

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.7876T>C (p.Trp2626Arg)

HGVS:

NC_000013.11:g.32362593T>C
NG_012772.3:g.52114T>C
NM_000059.4:c.7876T>CMANE SELECT
NP_000050.2:p.Trp2626Arg
NP_000050.3:p.Trp2626Arg
LRG_293t1:c.7876T>C
LRG_293:g.52114T>C
LRG_293p1:p.Trp2626Arg
NC_000013.10:g.32936730T>C
NM_000059.3:c.7876T>C

Protein change:

W2626R

Links:

dbSNP: rs1060502459

NCBI 1000 Genomes Browser:

rs1060502459

Molecular consequence:

NM_000059.4:c.7876T>C - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001189370	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 12, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12228710, 17100994, 25085752, 29884841 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001189370

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 12, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer.

Han SH, Lee KR, Lee DG, Kim BY, Lee KE, Chung WS.

Clin Genet. 2006 Dec;70(6):496-501.

PubMed [citation]

PMID:: 17100994

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV001189370.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.W2626R pathogenic mutation (also known as c.7876T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7876. The tryptophan at codon 2626 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in two Korean individuals diagnosed with sporadic breast cancer and was not detected in 167 controls (Han SH et al. Clin. Genet. 2006 Dec; 70(6):496-501). A close-match alteration at this codon, p.W2626C, has been reported in individuals with hereditary breast and ovarian cancer syndrome and Fanconi Anemia and was found deleterious in numerous functional assays; however one study found the close-match variant to be hypomorphic (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Konecny M et al. Breast Cancer Res.Treat. 2011 Feb;126:119-30; Wagner JE et al. Blood. 2004 Apr;103:3226-9; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). This alteration is deleterious in a homology directed repair assay (Hart SN et al. Genet. Med. 2019 01;21:71-80). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Yang H et al. Science. 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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