NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Aug 10, 2015
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000077422.20

Allele description [Variation Report for NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val)]

NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val)

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.7988A>T (p.Glu2663Val)

HGVS:

NC_000013.11:g.32363190A>T
NG_012772.3:g.52711A>T
NM_000059.4:c.7988A>TMANE SELECT
NP_000050.2:p.Glu2663Val
NP_000050.3:p.Glu2663Val
LRG_293t1:c.7988A>T
LRG_293:g.52711A>T
LRG_293p1:p.Glu2663Val
NC_000013.10:g.32937327A>T
NM_000059.3:c.7988A>T
U43746.1:n.8216A>T
p.E2663V

Nucleotide change:

8216A>T

Protein change:

E2663V

Links:

dbSNP: rs80359031

NCBI 1000 Genomes Browser:

rs80359031

Molecular consequence:

NM_000059.4:c.7988A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000109220	Sharing Clinical Reports Project (SCRP)	no assertion criteria provided	Pathogenic (Feb 24, 2012)	germline	clinical testing
SCV000147242	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Uncertain significance (May 29, 2002)	germline	clinical testing
SCV000244478	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015))	Pathogenic (Aug 10, 2015)	germline	curation	PubMed (1) [See all records that cite this PMID] ENIGMA BRCA1/2 Classification Criteria (2015), Citation Link,
SCV000327790	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000592166	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV002556660	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 30, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20513136, 29446198, 25741868
SCV004845584	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 16489001, 17924331, 18446624, 18451181, 18607349, 20104584, 20215541, 20513136, 21965345, 21990134, 23242139, 25452441, 33439686, 33808557, 25741868
SCV005045916	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 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	1	18	not provided	108544	not provided	clinical testing, curation
not provided	germline	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	6	not provided	not provided	6	not provided	clinical testing
Western European	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
Western European, English	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH, Thomassen M, Weitzel JN, Chan TL, Couch FJ, Goldgar DE, Kruse TA, Palmero EI, Park SK, Torres D, van Rensburg EJ, McGuffog L, Parsons MT, et al.

Hum Mutat. 2018 May;39(5):593-620. doi: 10.1002/humu.23406. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29446198
PMCID:: PMC5903938

Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.

Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, et al.

Cancer Res. 2006 Feb 15;66(4):2019-27.

PubMed [citation]

PMID:: 16489001

See all PubMed Citations (16)

Details of each submission

From Sharing Clinical Reports Project (SCRP), SCV000109220.4

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	6	not provided	not provided		not provided	not provided	not provided	not provided

From Breast Cancer Information Core (BIC) (BRCA2), SCV000147242.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided
2	Western European	2	not provided	not provided	clinical testing	not provided
3	Western European, English	1	not provided	not provided	clinical testing	not provided

#	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		6	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), SCV000244478.1

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

Description

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

#	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 Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000327790.4

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

#	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	18	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592166.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

The BRCA2 p.Glu2663Val variant has been identified in 4/5646 proband chromosomes (frequency 0.001) of individuals with breast and/or ovarian cancer, and was not identified in 360 control chromosomes, increasing the likelihood this variant may have clinical significance (Akbari_2011_21965345, Borg_2010_20104584, Chenevix-Trench_2006_16489001, Sanz_2010_20215541, Walker_2010_20513136). The variant is listed in the dbSNP database (ID: rs80359031), but no frequency information was provided, and so the prevalence of this variant in the general population is not known. It has been reported in the BIC (9x) database as a variant of unknown significance. The p.Glu2663 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Glu2663Val variant may impact the protein. Additionally, computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts this variant could potentially generate a cryptic splice site; however, these in silico tools are not predictive enough to assume pathogenicity. Functional studies evaluating splicing predict this variant to be deleterious (Capanu_2011_21520273, Farrugia_2008_18451181, Karachin_2008_19043619, Kuznetsov_2008_16489001, Lindor_2012_21990134); Farrugia et al 2008 demonstrated this variant results in skiipping of exon 18 and is predicted to cause a premature truncation of the BRCA2 protein. However, one study evaluating LOH in tumours identified this variant on the lost allele suggesting neutrality (Chenevix-Trench_2006_16489001). Cosegregation analysis based on data compiled by Myriad Genetics calculated this variant to have odds of 233:1 in favour of causality (Easton_2007_17924331). The variant has been shown to segregate with cancer in multiple families in Myriad's internal data (personal communication). In summary, based on the above information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		6	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556660.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The BRCA2 c.7988A>T variant is classified as Pathogenic (PS3, PS4, PP3, PP5) The BRCA2 c.7988A>T variant is a single nucleotide change in the BRCA2 gene, which is predicted to change the amino acid glutamic acid at position 2663 in the protein to valine. The variant has been reported in probands with a clinical presentation of breast and/or ovarian cancer (PMID:29446198) (PS4). Well-established functional studies show a deleterious effect of this variant (PMID:20513136) (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). Splicing predicitors predict abberrant splicing (introduction of donor site), resulting in exon skipping (exon19). The variant has been reported in dbSNP (rs80359031) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52462).

#	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 All of Us Research Program, National Institutes of Health, SCV004845584.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (15)

Description

This missense variant replaces glutamic acid with valine at codon 2663 in the DNA binding domain 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 the mutant protein to be incapable of complementing BRCA2-deficiency in mouse embryonic stem cells (PMID: 18607349) and to exhibit reduced homologous DNA repair activity (PMID: 20513136). In addition, multiple RNA studies have shown that this variant affects RNA splicing and results in the production of transcripts lacking the entire or partial exon 18, or both exons 17 and 18, all predicted to cause premature protein truncation (PMID: 18451181, 20215541, 20513136). The amount of full length transcript produced from the mutant allele was greater than that of aberrant transcripts. However, the ratio of aberrant transcript to full length transcripts was higher in carrier individuals than in non-carrier individuals of this variant (PMID: 20513136). These functional study results indicate that this variant inactivates BRCA2 gene function, both by disrupting protein function and by dysregulating RNA splicing. This variant has been reported in over ten individuals affected with breast cancer, ovarian cancer or pancreatic cancer (PMID: 16489001, 17924331, 18451181, 18446624, 20104584, 20513136, 21965345, 23242139, 25452441, 33808557, 33439686; Color internal data). The variant has been shown to segregate with cancer in multiple families (ClinVar SCV000592166.2) and determined to have a high probability of being disease-causing by multifactorial likelihood analysis using computational prediction, functional study data and genetic data (PMID: 17924331, 18451181, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, SCV005045916.1

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

Description

PM2_Supporting; PP1, PP3; PS3; Expert panel

#	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

Last Updated: Nov 24, 2024

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