NM_000059.4(BRCA2):c.8350C>T (p.Arg2784Trp) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jan 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000045487.26

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)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073500	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16683254, 27616075, 30032850, 34350294, 21520333, 33609447, 18451181, 23108138, 29884841, 29988080, 33293522, 28492532
SCV001363256	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 19200354, 18451181, 19043619, 24323938, 23108138, 16683254, 25447315, 25782689, 27616075, 29988080, 29884841, 29394989, 30447919, 30032850, 31060523, 31409081, 31742824, 33609447, 34350294, 35736817, 36721989, 34970085, 35762214 Citation Link,
SCV001478299	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 10, 2018)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 23108138, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000073500

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001363256

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 24, 2023)

germline

clinical testing

PubMed (23)
[See all records that cite these PMIDs]

Citation Link,

SCV001478299

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 10, 2018)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

PMID:: 21520333

A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays.

Biswas K, Lipton GB, Stauffer S, Sullivan T, Cleveland L, Southon E, Reid S, Magidson V, Iversen ES Jr, Sharan SK.

NPJ Genom Med. 2020 Dec 8;5(1):52. doi: 10.1038/s41525-020-00158-5.

PubMed [citation]

PMID:: 33293522
PMCID:: PMC7722754

See all PubMed Citations (27)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000073500.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2784 of the BRCA2 protein (p.Arg2784Trp). This variant is present in population databases (rs80359075, gnomAD 0.006%). This variant has been observed in individuals affected with breast, ovarian, and lung cancer (PMID: 16683254, 27616075, 30032850, 34350294). This variant may be associated with reduced penetrance of hereditary breast and ovarian cancer syndrome based on statistical analysis (external communication). In addition, this variant has been observed in individuals with Fanconi anemia (PMID: 21520333, external communication). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38155). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 23108138, 29884841, 29988080, 33293522). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363256.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (23)

Description

Variant summary: BRCA2 c.8350C>T (p.Arg2784Trp) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251430 control chromosomes. c.8350C>T has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (e.g. van der Hout_2006, Farrugia_2008, Garcia_2009, Vail_2015, Kraus_2017, daCosta_2019, Machackova_2019, Shao_2020, Wu_2021), Fanconi anemia (e.g. Radulovic_2023), or other cancers (e.g. Donner_2018, Sirak_2021, Xia_2022). Several publications report experimental evidence evaluating an impact on protein function (e.g. Farrugia_2008, Guidugli_2013, Guidugli_2018, Mesman_2019, Richardson_2021, Hu_2022) including significantly impaired homology directed repair activity meaured by HDR assays. The following publications have been ascertained in the context of this evaluation (PMID: 30032850, 18451181, 19200354, 29394989, 23108138, 24323938, 29884841, 35736817, 19043619, 27616075, 25447315, 31409081, 29988080, 36721989, 33609447, 31742824, 34970085, 25782689, 34350294, 35762214, 31060523, 30447919, 16683254). 19 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=3), likely pathogenic (n=13), or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From Cancer Variant Interpretation Group UK, Institute of Cancer Research, London, SCV001478299.1

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

Description

Data used in classification: This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (20.3) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified on ClinVar as likely pathogenic by accredited USA diagnostic laboratory GeneDx, 2017 (PP5_sup). Data not used in classification: The variant was observed in 1 independent UK family undergoing clinical diagnostic BRCA1/BRCA2 testing for HBOC according to diagnostic criteria, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (1/16,600 in familial cases against 1/55,836 gnomAD NFE controls) 2-sided Fishers exact: pexact= 0.4. The frequency of this variant is 2/67,272 individuals (remainder of the gnomAD population).

#	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 10, 2024

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