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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 30, 2024
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:: RCV000045336.26

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]

Observations:

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073349	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11802209, 15070707, 16115142, 20104584, 21138478, 21203900, 22666503, 25085752, 17924331, 21719596, 21990134, 23108138, 25146914, 28492532
SCV000494423	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 28, 2019)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 21990134, 20104584, 17924331, 21520273, 11802209, 21719596, 21203900, 22666503, 16115142, 15070707, 25146914, 25085752, 29988080, 29339979 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000605791	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jul 20, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17924331, 17100994, 26733283, 25085752, 25146914, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000073349

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV000494423

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 28, 2019)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000605791

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jul 20, 2017)

germline

clinical testing

PubMed (6)
[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	not provided	2	2	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hepatoblastoma in a 4-year-old girl with Fanconi anaemia.

Kopic S, Eirich K, Schuster B, Hanenberg H, Varon-Mateeva R, Rittinger O, Schimpl G, Schindler D, Jones N.

Acta Paediatr. 2011 May;100(5):780-3. doi: 10.1111/j.1651-2227.2010.02116.x. Epub 2011 Jan 12.

PubMed [citation]

PMID:: 21138478

A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.

Guidugli L, Pankratz VS, Singh N, Thompson J, Erding CA, Engel C, Schmutzler R, Domchek S, Nathanson K, Radice P, Singer C, Tonin PN, Lindor NM, Goldgar DE, Couch FJ.

Cancer Res. 2013 Jan 1;73(1):265-75. doi: 10.1158/0008-5472.CAN-12-2081. Epub 2012 Oct 29.

PubMed [citation]

PMID:: 23108138
PMCID:: PMC3537884

See all PubMed Citations (20)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000073349.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 2626 of the BRCA2 protein (p.Trp2626Cys). This variant is present in population databases (rs80359013, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and Fanconi anemia (PMID: 11802209, 15070707, 16115142, 20104584, 21138478, 21203900, 22666503, 25085752). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38125). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 17924331, 21719596, 21990134, 23108138, 25146914). For these reasons, this variant has been classified as Pathogenic.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000494423.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

BRCA2 c.7878G>C (p.Trp2626Cys) results in a non-conservative amino acid change in the helical domain (IPR015252). Five in-silico tools predict a damaging effect. Observed at a frequency of 7.9e-06 in 251676 control chromosomes. Reported in individuals with Hereditary Breast and Ovarian Cancer (PMID's listed) and in trans with another BRCA2 variant (2041insA) in individuals with Fanconi Anemia (PMID's listed and BIC database). Several publications report experimental evidence demonstrating an inability to complement the cell lethal phenotype induced by loss of endogenous mouse BRCA2 (PMID's listed). One expert panel (ENIGMA) and ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was re-classified as pathogenic.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000605791.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Trp2626Cys variant in BRCA2 has been reported in >16 individuals with BRCA 2-associated cancers (Han 2006, Petersen 2016, Breast Cancer Information Core). This variant has been identified in 2/66726 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359013) . However, this frequency is low enough to be consistent with the frequency of h ereditary breast and ovarian cancer (HBOC) in the general population. In vitro f unctional studies provide some evidence that the p.Trp2626Cys may impact protein function (Hendriks 2014). Computational prediction tools and conservation analy sis suggest that the p.Trp2626Cys variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In addition, this variant was classified as Pathogenic on Aug 10, 2016 by the ClinGen-approved EN IGMA expert panel (ClinVar SCV000244475.1). In summary, although additional stud ies are required to fully establish its clinical significance, the p.Trp2626Cys variant is likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Nov 3, 2024

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