NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 20, 2023
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:: RCV000163025.22

Allele description [Variation Report for NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys)]

NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys)

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.7878G>C (p.Trp2626Cys)

HGVS:

NC_000013.11:g.32362595G>C
NG_012772.3:g.52116G>C
NM_000059.4:c.7878G>CMANE SELECT
NP_000050.2:p.Trp2626Cys
NP_000050.3:p.Trp2626Cys
LRG_293t1:c.7878G>C
LRG_293:g.52116G>C
LRG_293p1:p.Trp2626Cys
NC_000013.10:g.32936732G>C
NM_000059.3:c.7878G>C
U43746.1:n.8106G>C
p.W2626C

Nucleotide change:

8106G>C

Protein change:

W2626C

Links:

dbSNP: rs80359013

NCBI 1000 Genomes Browser:

rs80359013

Molecular consequence:

NM_000059.4:c.7878G>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
SCV000213513	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 11802209, 15070707, 17924331, 19043619, 20104584, 21138478, 21203900, 21719596, 21990134, 21990165, 22666503, 23108138, 25085752, 25146914, 26014432, 27194814, 29478780, 29988080, 30720243 Citation Link,
SCV000689074	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 11802209, 15070707, 16115142, 20104584, 21138478, 21203900, 21719596, 22666503, 23108138, 25146914, 26014432, 27194814, 29884841, 29988080, 33471991, 33978741, 34906479, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213513

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 20, 2023)

germline

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

Citation Link,

SCV000689074

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 16, 2023)

germline

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

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

A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.

Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, Tavtigian SV, Monteiro AN, Iversen ES, Couch FJ, Goldgar DE.

Am J Hum Genet. 2007 Nov;81(5):873-83. Epub 2007 Sep 6.

PubMed [citation]

PMID:: 17924331
PMCID:: PMC2265654

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 19043619
PMCID:: PMC2587343

See all PubMed Citations (25)

Details of each submission

From Ambry Genetics, SCV000213513.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

The p.W2626C pathogenic mutation (also known as c.7878G>C), located in coding exon 16 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7878. The tryptophan at codon 2626 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been described in families with phenotypes consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Meindl A et al. Int. J. Cancer 2002 Feb;97:472-80; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Konecny M et al. Breast Cancer Res. Treat. 2011 Feb;126:119-30; Meyer P et al. PLoS ONE 2012;7:e38361; Winter C et al. Ann. Oncol. 2016 Aug;27:1532-8; Polsler L et al. Eur. J. Hum. Genet. 2016 Feb;24:258-62). This variant has also been identified in two unrelated patients with Fanconi Anemia (Wagner JE et al. Blood. 2004 Apr;103:3226-9; Kopic S et al. Acta Paediatr. 2011 May;100:780-3). In one of these patients, this alteration was confirmed to be in trans with a frameshift mutation (Wagner JE et al. Blood. 2004 Apr;103:3226-9). Functional assays evaluating homology-directed DNA break repair (HDR), embryonic stem cell rescue viability, susceptibility to DNA damaging agents, chromosomal aberration, and RAD51 foci have all indicated deficient function in BRCA2 p.W2626C mutants (Biswas K et al. Blood. 2011 Sep;118:2430-42; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Hendriks G et al. Hum. Mutat. 2014 Nov;35:1382-91; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med., 2018 Jul;). However, one paper describes this as a hypomorphic variant based on a history weighting algorithm (Pruss D et al. Breast Cancer Res. Treat., 2014 Aug;147:119-32). 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. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000689074.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

This missense variant replaces tryptophan with cysteine at codon 2626 in the DNA binding of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant showed loss of function in homology-directed repair and DNA damage response assays and the complementation of Brca2-deficient mouse embryonic stem cells, and it impaired nuclear localization of BRCA2 protein (PMID: 21719596, 23108138, 25146914, 29884841, 29988080, 33978741). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 20104584, 21203900, 22666503, 26014432, 27194814) and this variant also has been detected in a breast cancer case-control meta-analysis in 7/60466 cases and 5/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000238). In a study of 34 families, this variant has shown reduced penetrance and lower risk of breast cancer compared with other pathogenic variants in the BRCA1 and BRCA2 genes (PMID: 34906479). This variant has also been observed in two unrelated, biallelic individuals affected with Fanconi anemia, who were compound heterozygous with pathogenic variant in the same gene (PMID: 15070707; 16115142, 21138478), indicating that this variant contribute to disease. This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic with reduced penetrance.

#	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: Nov 24, 2024

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