NM_000059.4(BRCA2):c.8350C>T (p.Arg2784Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jul 25, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000392114.28

Allele description [Variation Report for NM_000059.4(BRCA2):c.8350C>T (p.Arg2784Trp)]

NM_000059.4(BRCA2):c.8350C>T (p.Arg2784Trp)

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.8350C>T (p.Arg2784Trp)

HGVS:

NC_000013.11:g.32370420C>T
NG_012772.3:g.59941C>T
NM_000059.4:c.8350C>TMANE SELECT
NP_000050.2:p.Arg2784Trp
NP_000050.3:p.Arg2784Trp
LRG_293t1:c.8350C>T
LRG_293:g.59941C>T
LRG_293p1:p.Arg2784Trp
NC_000013.10:g.32944557C>T
NM_000059.3:c.8350C>T
U43746.1:n.8578C>T
p.Arg2784Trp
p.R2784W

Nucleotide change:

8578C>T

Protein change:

R2784W

Links:

dbSNP: rs80359075

NCBI 1000 Genomes Browser:

rs80359075

Molecular consequence:

NM_000059.4:c.8350C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329141	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 25, 2023)	germline	clinical testing	Citation Link,
SCV001133931	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Oct 13, 2022)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 34350294, 33609447, 16683254, 29988080, 21638052, 33471991, 18451181, 19200354, 23108138, 24323938, 31409081, 33293522, 27616075, 29394989, 29884841, 26467025
SCV002010309	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002022079	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799562	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Mar 10, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identifying Sequence Variants of 18 Hereditary Ovarian Cancer-Associated Genes in Chinese Epithelial Ovarian Cancer Patients.

Wu X, Chen Z, Ren P, Zhao X, Tang D, Geng H, Xu X, Zhao W.

Biomed Res Int. 2021;2021:5579543. doi: 10.1155/2021/5579543.

PubMed [citation]

PMID:: 34350294
PMCID:: PMC8328723

Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance.

Richardson ME, Hu C, Lee KY, LaDuca H, Fulk K, Durda KM, Deckman AM, Goldgar DE, Monteiro ANA, Gnanaolivu R, Hart SN, Polley EC, Chao E, Pesaran T, Couch FJ.

Am J Hum Genet. 2021 Mar 4;108(3):458-468. doi: 10.1016/j.ajhg.2021.02.005. Epub 2021 Feb 19.

PubMed [citation]

PMID:: 33609447
PMCID:: PMC8008494

See all PubMed Citations (17)

Details of each submission

From GeneDx, SCV000329141.9

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

Description

Published functional studies demonstrate a damaging effect: displayed reduced homologous recombination repair activity in multiple homology-directed DNA break repair assays as well as poor survival in mouse embryonic stem cell assay (Farrugia et al., 2008; Guidugli et al., 2013; Mesman et al., 2018; Hart et al., 2019; Biswas et al., 2020; Hu et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8578C>T; This variant is associated with the following publications: (PMID: 21638052, 25447315, 31060523, 34687993, 18451181, 19200354, 16683254, 19043619, 25782689, 27616075, 30032850, 10923033, 18951461, 29988080, 12228710, 16205630, 26145171, 22194698, 24323938, 31409081, 33293522, 29884841, 34350294, 32719484, 33609447, 35665744, 36387127, Akolkar2022[preprint], 33471991, 35736817, 36099812, 31742824, 35762214, 35753512, 23108138, 29394989)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001133931.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The frequency of this variant in the general population, 0.000008 (2/251430 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. It has been reported in families with breast and/or ovarian cancer in the published literature (PMIDs: 27616075 (2016), 16683254 (2006), 21638052 (2011), 31060523 (2019), and 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)), as well as in one individual affected with lung cancer (PMID: 30032850 (2018)). Multiple functional studies have reported that this variant impairs homology-directed DNA break repair activity and shows reduced cell survival compared to wild type, however it does not affect centrosome amplification (PMIDs: 18451181 (2008), 23108138 (2013), 29394989 (2018), 29988080 (2018), and 33293522 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

#	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 Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010309.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002022079.3

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799562.2

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

Description

The BRCA2 c.8350C>T; p.Arg2784Trp variant (rs80359075), also known as 8578C>T, is reported in the literature in several individuals and families affected with breast, ovarian, or lung cancer (Brandao 2011, Donner 2018, Gomez Garcia 2009, Kraus 2017, van der Hout 2006). This variant is also reported in ClinVar (Variation ID: 38155), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2784 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.738). Functional analyses of the variant protein show impaired homology-directed DNA break repair activity (Farrugia 2008, Guidugli 2013, Hart 2019, Mesman 2019). Based on available information, this variant is considered to be likely pathogenic. References: Brandao RD et al. Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing. Breast Cancer Res Treat. 2011 Oct;129(3):971-82. PMID: 21638052. Donner I et al. Germline mutations in young non-smoking women with lung adenocarcinoma. Lung Cancer. 2018 Aug;122:76-82. PMID: 30032850. Farrugia DJ et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. PMID: 18451181. Gomez Garcia EB et al. A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res. 2009;11(1):R8. PMID: 19200354. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. PMID: 23108138. Hart SN et al. Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models. Genet Med. 2019 Jan;21(1):71-80. PMID: 29884841. Kraus C et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer. 2017 Jan 1;140(1):95-102. PMID: 27616075. Mesman RLS et al. The functional impact of variants of uncertain significance in BRCA2. Genet Med. 2019 Feb;21(2):293-302. PMID: 29988080. van der Hout AH et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006 Jul;27(7):654-66. PMID: 16683254.

#	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: May 19, 2024

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