NM_000059.4(BRCA2):c.7878G>C (p.Trp2626Cys) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Aug 5, 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:: RCV000482471.48

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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ABHD12B abhydrolase domain containing 12B [Homo sapiens]
ABHD12B abhydrolase domain containing 12B [Homo sapiens]
Gene ID:145447

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000296697	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 3, 2022)	unknown	clinical testing	PubMed (41) [See all records that cite these PMIDs] 21203900, 20104584, 25085752, 11802209, 16115142, 21138478, 25146914, 25583207, 25782689, 26566862, 27194814, 27495310, 30720243, 29988080, 29339979, 26733283, 26014432, 32853339, 32444794, 32885271, 34906479, 33978741, 34680878, 31853058, 29394989, 30696104, 30728895, 29884841, 30257646, 17924331, 16825431, 21520273, 15070707, 19043619, 21719596, 21990134, 22666503, 23108138, 24323938, 26467025, 26295337
SCV000564795	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 20, 2023)	germline	clinical testing	Citation Link,
SCV001249493	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV001447631	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002551646	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003814449	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005199825	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 6, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005328471	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia.

Konecny M, Milly M, Zavodna K, Weismanova E, Gregorova J, Mlkva I, Ilencikova D, Kausitz J, Bartosova Z.

Breast Cancer Res Treat. 2011 Feb;126(1):119-30. doi: 10.1007/s10549-010-1325-x. Epub 2011 Jan 4.

PubMed [citation]

PMID:: 21203900

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

See all PubMed Citations (42)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296697.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (41)

Description

The frequency of this variant in the general population, 0.000008 (2/251276 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant is described as a pathogenic variant with reduced penetrance, carrying a lower breast cancer risk than other BRCA2 pathogenic variants (PMID: 34906479 (2022)). It has been reported in individuals or families with breast cancer (PMIDs: 34680878 (2021), 34906479 (2022), 30728895 (2019), 30257646 (2018), 29339979 (2018), 27194814 (2016), 26014432 (2015), 22666503 (2012), 21203900 (2011)) or prostate cancer (PMID: 32853339 (2021)). This variant has also been reported in trans with a second pathogenic BRCA2 variant in patients with Fanconi anemia (PMIDs: 21138478 (2011), 15070707 (2004)). Published functional studies indicate that this variant impairs BRCA2 protein activity (PMIDs: 33978741 (2021), 32444794 (2020), 30696104 (2019), 29884841 (2019), 29394989 (2018), 29988080 (2018), 25146914 (2014), 23108138 (2013), 21719596 (2011)). Based on the available information, 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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000564795.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Multifactorial studies suggest this variant is associated with breast and ovarian cancer, but may confer lower risks than typical BRCA2 pathogenic variants (Biswas et al., 2011; Lindor et al., 2012; Pruss et al., 2014; Li et al., 2020; Li et al., 2022); Published functional studies demonstrate a damaging effect: impaired homologous recombination and sensitivity to PARP inhibitors (Biswas et al., 2011; Stoepker et al., 2015; Guidugli et al., 2018; Ikegami et al., 2020; Lee et al., 2021; Iversen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 8106G>C; This variant is associated with the following publications: (PMID: 23108138, 17924331, 22666503, 20104584, 27194814, 29478780, 31409081, 29446198, 30291343, 12228710, 25146914, 25583207, 16115142, 21719596, 19043619, 24323938, 21520273, 25085752, 16825431, 18951461, 25782689, 27767231, 28315974, 21138478, 26566862, 28866612, 21203900, 21990165, 29339979, 28541631, 30257646, 30728895, 29988080, 30720243, 31853058, 30696104, 32444794, 29884841, 31263571, 30702160, 31825140, 32719484, 29625052, 32885271, 32853339, 30787465, 32295079, 34906479, 34680878, 29394989, 21990134, 15070707, 29922827, 31794323, 35665744, 33978741, 34308104)

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

From CeGaT Center for Human Genetics Tuebingen, SCV001249493.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

BRCA2: PS3, PM1, PS4:Moderate, PM2:Supporting, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447631.1

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

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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002551646.6

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

#	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 Revvity Omics, Revvity, SCV003814449.2

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

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199825.1

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

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

From Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital, SCV005328471.1

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

#	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 3, 2024

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