VCV000038125.75 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

31 submissions

29 submitters

10 conditions

Reviewed by expert panel

Pathogenic

Aug 2015 by Evidence-based…

for Breast-ovarian cancer, familial 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 38125 Accession: VCV000038125.75

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32362595 (GRCh38) [ NCBI UCSC ] 13: 32936732 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2014	Nov 24, 2024	Aug 10, 2015

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.7878G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Trp2626Cys	missense
NC_000013.11:g.32362595G>C
NC_000013.10:g.32936732G>C
NG_012772.3:g.52116G>C
LRG_293:g.52116G>C
LRG_293t1:c.7878G>C	LRG_293p1:p.Trp2626Cys
U43746.1:n.8106G>C

... more HGVS ... less HGVS

Protein change

W2626C

Other names

8106G>C

Canonical SPDI

NC_000013.11:32362594:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA025319 dbSNP: rs80359013 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18985	19144

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (10)	reviewed by expert panel	Aug 10, 2015	RCV000031707.24
Hereditary breast ovarian cancer syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 30, 2024	RCV000045336.26
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 20, 2023	RCV000163025.22
Malignant tumor of breast	Likely pathogenic (1)	no assertion criteria provided	-	RCV001357728.10
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Aug 5, 2024	RCV000482471.49
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 22, 2024	RCV002288525.11
Breast and/or ovarian cancer	Pathogenic (1)	no assertion criteria provided	Jun 11, 2019	RCV001271059.9
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Oct 16, 2024	RCV004783730.1
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Likely pathogenic (1)	criteria provided, single submitter	Feb 8, 2022	RCV002504846.8
Uterine corpus cancer	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128132.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 10, 2015)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000244475.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 23108138 Other databases http://hci-exlovd.hci.utah.edu/v… http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.7878G%3EC Comment: IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on … (more) IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 (less)
Pathogenic (Jun 03, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296697.4 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (40) PubMed: 26295337‚ 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 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 20, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000605791.2 First in ClinVar: Apr 16, 2017 Last updated: Dec 26, 2017	Publications: PubMed (5) PubMed: 17924331‚ 17100994‚ 26733283‚ 25085752‚ 25146914 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 2
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447631.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579195.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4_MOD, PM3, PM2_SUP, PP1, PP3	Number of individuals with the variant: 5 Sex: female
Pathogenic (Sep 20, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000564795.10 First in ClinVar: Apr 27, 2017 Last updated: Sep 30, 2023	Comment: 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., … (more) 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) (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213635.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551646.6 First in ClinVar: Jul 30, 2022 Last updated: Aug 04, 2024
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429417.2 First in ClinVar: Aug 17, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PS3,PP1_STR,PS4_MOD,PM3_SUP, PM2_SUP Clinical Features: Macrocephaly (present) , Increased head circumference (present) Sex: female
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249493.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: BRCA2: PS3, PM1, PS4:Moderate, PM2:Supporting, PP3 Number of individuals with the variant: 5
Pathogenic (Oct 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005397059.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Clinical Features: Family history of cancer (present) , Ductal carcinoma in situ (present) Sex: female
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000327755.4 First in ClinVar: Sep 29, 2015 Last updated: Dec 11, 2022
Likely pathogenic (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605699.3 First in ClinVar: Sep 29, 2015 Last updated: Dec 11, 2022	Number of individuals with the variant: 3
Pathogenic (Oct 28, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494423.3 First in ClinVar: Jul 01, 2016 Last updated: Dec 11, 2022	Publications: PubMed (14) PubMed: 21990134‚ 20104584‚ 17924331‚ 21520273‚ 11802209‚ 21719596‚ 21203900‚ 22666503‚ 16115142‚ 15070707‚ 25146914‚ 25085752‚ 29988080‚ 29339979 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 15, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488157.2 First in ClinVar: Sep 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (6) PubMed: 25146914‚ 23108138‚ 21719596‚ 21203900‚ 11802209‚ 20104584
Likely pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002816654.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jul 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814449.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000073349.12 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 28492532‚ 11802209‚ 15070707‚ 16115142‚ 20104584‚ 21138478‚ 21203900‚ 22666503‚ 25085752‚ 17924331‚ 21990134‚ 21719596‚ 23108138‚ 25146914 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000689074.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (17) PubMed: 11802209‚ 15070707‚ 16115142‚ 20104584‚ 21138478‚ 21203900‚ 21719596‚ 22666503‚ 23108138‚ 25146914‚ 26014432‚ 27194814‚ 29884841‚ 29988080‚ 33471991‚ 33978741‚ 34906479 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000213513.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (19) PubMed: 11802209‚ 15070707‚ 17924331‚ 19043619‚ 20104584‚ 21138478‚ 21203900‚ 21719596‚ 21990134‚ 21990165‚ 22666503‚ 23108138‚ 25085752‚ 25146914‚ 26014432‚ 27194814‚ 29478780‚ 29988080‚ 30720243 Comment: 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 … (more) 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. (less)
Pathogenic (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005045982.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: PS3; PP3; PM1; Expert panel
Pathogenic (Oct 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199825.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital Accession: SCV005328471.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024
Pathogenic (Apr 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414162.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (14) PubMed: 15070707‚ 17100994‚ 17924331‚ 20104584‚ 21138478‚ 21203900‚ 21990134‚ 22666503‚ 25085752‚ 26014432‚ 27194814‚ 29884841‚ 29988080‚ 32444794 Comment: PP4_strong, PM3_strong, PS3 Number of individuals with the variant: 2
Likely pathogenic (Dec 19, 2012)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000054314.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2014
Pathogenic (Mar 02, 2020)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV004243787.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Uncertain significance (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147208.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 5 Observation 2: Number of individuals with the variant: 2 Geographic origin: Austria Observation 3: Number of individuals with the variant: 5 Ethnicity/Population group: Western European Observation 4: Number of individuals with the variant: 1 Ethnicity/Population group: Western Europeanan, Central/Eastern European
Likely pathogenic (Feb 11, 2015)	no assertion criteria provided (clinical testing) Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Institute of Human Genetics, Medical University Innsbruck Study: BRCA-Tyrol Accession: SCV000212029.1 First in ClinVar: Mar 03, 2015 Last updated: Mar 03, 2015 Comment: BRCA-mutation spectrum Western Austria
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451881.1 First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 3 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001553281.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The BRCA2 p.Trp2626Cys variant was identified in 4 of 7208 proband chromosomes (frequency: 0.0006) from individuals or families with contralateral and unilateral breast cancers, and … (more) The BRCA2 p.Trp2626Cys variant was identified in 4 of 7208 proband chromosomes (frequency: 0.0006) from individuals or families with contralateral and unilateral breast cancers, and was not identified in 2996 control chromosomes from healthy individuals (Borg 2010 PMID:20104584, Pruss 2014 PMID:25085752, Capanu 2011 PMID:21520273, Petersen 2016 PMID:26733283). The variant has also been identified in at least one patient with Fanconi anemia who also harboured a BRCA2 frameshift pathogenic variant (Stoepker 2015 PMID:25583207). In a study done to classify unknown variants, the variant was submitted to web-based algorithms using Align-GVGD, Grantham Variation and Grantham Deviation scores and found to be class (C65) of substitutions, which is most likely to interfere with function and was scored as possibly deleterious (Borg 2010 PMID:20104584). Furthermore studies classified the variant as deleterious based on a loss of DNA repair function identified through function studies (Biswas 2011 PMID:21719596, Guidugli 2013 PMID: 23108138, Hendriks 2014 PMID:25146914). The variant was shown to be sensitive to PARP inhibitors when present in a cell line derived from a patient with Fanconi anemia (Stoepker 2015). In addition Lindor et al. 2011 (PMID:21990134) determined the variant to be pathogenic (48.14 possibility of causality) when they weighted together segregation data, co-occurrence with pathogenic variants, personal and family history, and tumor pathology. However the above study by Biswas et al. 2011 demonstrated that the variant may be hypomorphic as it was able to recuse lethality in embryonic stem cells (notably in a similar experiment in the Hendrick et al. study the variant did not rescue lethality), and Pruss et al. 2014 also classified the variant as hypomorphic based on clinic history weighting algorithm. The variant was identified in dbSNP (ID: rs80359013 â€šÃ„ÃºWith Pathogenic Alleleâ€šÃ„Ã¹, in 1000 Genomes Project in 2 of 100000 chromosomes (frequency: 0.00002). The variant was also identified in the Exome Aggregation Consortium database (released Mar 14, 2016) in 2 of 121350 chromosomes (frequency: 0.00002) from a population of 2 of 66726 (0.00003) of European (Non-Finnish) alleles, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in GeneInsight-COGR by Trillum Health Partners 1x as Class 5, in Clinvar (pathogenic by ENIGMA, Quest, CIMBA, Counsyl, LMM, and Invitae, AND as likely pathogenic by LabCorp, GeneDx, Oslo University, Ambry, SCRP, and Medical University Innsbruck as well as Uncertain Significance by BIC). The variant is further identified in the BIC database 14X with unknown clinical importance, in the ARUP Laboratories BRCA Mutations Database 1x as definitely pathogenic, in the Fanconi Anemia Mutation Database (LOVD) 2x as predicted deleterious and 1x with reduced complementation. The variant was not listed in the COSMIC, MutDB, and UMD databases. The p.Trp2626 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (less)
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Uterine corpus cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804352.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The BRCA2 p.Trp2626Cys variant was identified in 4 of 7208 proband chromosomes (frequency: 0.0006) from individuals or families with contralateral and unilateral breast cancers, and was not identified in 2996 control chromosomes from healthy individuals (Borg 2010 PMID:20104584, Pruss 2014 PMID:25085752, Capanu 2011 PMID:21520273, Petersen 2016 PMID:26733283). The variant has also been identified in at least one patient with Fanconi anemia who also harboured a BRCA2 frameshift pathogenic variant (Stoepker 2015 PMID:25583207). In a study done to classify unknown variants, the variant was submitted to web-based algorithms using Align-GVGD, Grantham Variation and Grantham Deviation scores and found to be class (C65) of substitutions, which is most likely to interfere with function and was scored as possibly deleterious (Borg 2010 PMID:20104584). Furthermore studies classified the variant as deleterious based on a loss of DNA repair function identified through function studies (Biswas 2011 PMID:21719596, Guidugli 2013 PMID: 23108138, Hendriks 2014 PMID:25146914). The variant was shown to be sensitive to PARP inhibitors when present in a cell line derived from a patient with Fanconi anemia (Stoepker 2015). In addition Lindor et al. 2011 (PMID:21990134) determined the variant to be pathogenic (48.14 possibility of causality) when they weighted together segregation data, co-occurrence with pathogenic variants, personal and family history, and tumor pathology. However the above study by Biswas et al. 2011 demonstrated that the variant may be hypomorphic as it was able to recuse lethality in embryonic stem cells (notably in a similar experiment in the Hendrick et al. study the variant did not rescue lethality), and Pruss et al. 2014 also classified the variant as hypomorphic based on clinic history weighting algorithm. The variant was identified in dbSNP (ID: rs80359013 â€šÃ„ÃºWith Pathogenic Alleleâ€šÃ„Ã¹, in 1000 Genomes Project in 2 of 100000 chromosomes (frequency: 0.00002). The variant was also identified in the Exome Aggregation Consortium database (released Mar 14, 2016) in 2 of 121350 chromosomes (frequency: 0.00002) from a population of 2 of 66726 (0.00003) of European (Non-Finnish) alleles, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in GeneInsight-COGR by Trillum Health Partners 1x as Class 5, in Clinvar (pathogenic by ENIGMA, Quest, CIMBA, Counsyl, LMM, and Invitae, AND as likely pathogenic by LabCorp, GeneDx, Oslo University, Ambry, SCRP, and Medical University Innsbruck as well as Uncertain Significance by BIC). The variant is further identified in the BIC database 14X with unknown clinical importance, in the ARUP Laboratories BRCA Mutations Database 1x as definitely pathogenic, in the Fanconi Anemia Mutation Database (LOVD) 2x as predicted deleterious and 1x with reduced complementation. The variant was not listed in the COSMIC, MutDB, and UMD databases. The p.Trp2626 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.	Li H	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906479
The Importance of Extended Analysis Using Current Molecular Genetic Methods Based on the Example of a Cohort of 228 Patients with Hereditary Breast and Ovarian Cancer Syndrome.	Resch LD	Genes	2021	PMID: 34680878
Cancer-causing BRCA2 missense mutations disrupt an intracellular protein assembly mechanism to disable genome maintenance.	Lee M	Nucleic acids research	2021	PMID: 33978741
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.	Lerner-Ellis J	Journal of cancer research and clinical oncology	2021	PMID: 32885271
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
High-throughput functional evaluation of BRCA2 variants of unknown significance.	Ikegami M	Nature communications	2020	PMID: 32444794
Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.	Li H	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31853058
The effects of genomic germline variant reclassification on clinical cancer care.	Slavin TP	Oncotarget	2019	PMID: 30728895
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
GFP-Fragment Reassembly Screens for the Functional Characterization of Variants of Uncertain Significance in Protein Interaction Domains of the BRCA1 and BRCA2 Genes.	Caleca L	Cancers	2019	PMID: 30696104
The functional impact of variants of uncertain significance in BRCA2.	Mesman RLS	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29988080
Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.	Hart SN	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29884841
Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria.	Hoyer J	BMC cancer	2018	PMID: 30257646
Inherited DNA-Repair Defects in Colorectal Cancer.	AlDubayan SH	American journal of human genetics	2018	PMID: 29478780
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.	Guidugli L	American journal of human genetics	2018	PMID: 29394989
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.	Heramb C	Hereditary cancer in clinical practice	2018	PMID: 29339979
Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort.	Jarhelle E	Familial cancer	2017	PMID: 27495310
Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.	Winter C	Annals of oncology : official journal of the European Society for Medical Oncology	2016	PMID: 27194814
Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling.	Petersen AH	European journal of human genetics : EJHG	2016	PMID: 26733283
High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing.	Pölsler L	European journal of human genetics : EJHG	2016	PMID: 26014432
Molding BRCA2 function through its interacting partners.	Martinez JS	Cell cycle (Georgetown, Tex.)	2015	PMID: 26566862
Development and Validation of a Next-Generation Sequencing Assay for BRCA1 and BRCA2 Variants for the Clinical Laboratory.	Strom CM	PloS one	2015	PMID: 26295337
Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases.	Vail PJ	Journal of community genetics	2015	PMID: 25782689
DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity.	Stoepker C	DNA repair	2015	PMID: 25583207
An efficient pipeline for the generation and functional analysis of human BRCA2 variants of uncertain significance.	Hendriks G	Human mutation	2014	PMID: 25146914
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes.	Pruss D	Breast cancer research and treatment	2014	PMID: 25085752
Functional assays for analysis of variants of uncertain significance in BRCA2.	Guidugli L	Human mutation	2014	PMID: 24323938
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.	Guidugli L	Cancer research	2013	PMID: 23108138
BRCA2 mutations and triple-negative breast cancer.	Meyer P	PloS one	2012	PMID: 22666503
Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs.	Vallée MP	Human mutation	2012	PMID: 21990165
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).	Lindor NM	Human mutation	2012	PMID: 21990134
A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay.	Biswas K	Blood	2011	PMID: 21719596
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.	Capanu M	Genetic epidemiology	2011	PMID: 21520273
Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia.	Konecny M	Breast cancer research and treatment	2011	PMID: 21203900
Hepatoblastoma in a 4-year-old girl with Fanconi anaemia.	Kopic S	Acta paediatrica (Oslo, Norway : 1992)	2011	PMID: 21138478
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.	Karchin R	Cancer informatics	2008	PMID: 19043619
A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.	Easton DF	American journal of human genetics	2007	PMID: 17924331
Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.	Alter BP	Journal of medical genetics	2007	PMID: 16825431
Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer.	Han SH	Clinical genetics	2006	PMID: 17100994
Inherited FANCD1/BRCA2 exon 7 splice mutations associated with acute myeloid leukaemia in Fanconi anaemia D1 are not found in sporadic childhood leukaemia.	Barber LM	British journal of haematology	2005	PMID: 16115142
Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.	Wagner JE	Blood	2004	PMID: 15070707
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.	Meindl A	International journal of cancer	2002	PMID: 11802209
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.7878G%3EC	-	-	-	-
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Text-mined citations for rs80359013 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359013 ...