NM_000059.4:c.8350C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000059.4(BRCA2):c.8350C>T(p.Arg2784Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2784L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22U:5

Conservation

PhyloP100: 4.25

Publications

29 publications found

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 24 uncertain in NM_000059.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32370421-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 491350.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

PP5

Variant 13-32370420-C-T is Pathogenic according to our data. Variant chr13-32370420-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 38155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8350C>T	p.Arg2784Trp	missense_variant	Exon 19 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8350C>T	p.Arg2784Trp	missense_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7981C>T	p.Arg2661Trp	missense_variant	Exon 19 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*408C>T		non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*408C>T		3_prime_UTR_variant	Exon 18 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251430

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111646

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:6Uncertain:2

Jan 14, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Aug 06, 2021

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 28, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:5Uncertain:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Jan 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3, PS3 -

May 03, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (PMID: 18451181, 23108138, 29988080, 29884841, 33293522, 35736817); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates 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, 36721989, 31060523, 34687993, 18451181, 19200354, 16683254, 19043619, 25782689, 27616075, 30032850, 10923033, 18951461, 29988080, 12228710, 16205630, 26145171, 22194698, 24323938, 31409081, 33293522, 29884841, 34350294, 32719484, 33609447, 35665744, 38623065, 36387127, Akolkar2022[preprint], 33471991, 35736817, 36099812, 31742824, 35762214, 35753512, 23108138, 29394989) -

Mar 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.8350C>T (p.Arg2784Trp) variant has been reported in the published literature in families with breast and/or ovarian cancer in the published literature (PMIDs: 33471991 (2021), 31060523 (2019), 27616075 (2016), 21638052 (2011), 16683254 (2006), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)), as well as in one individual affected with lung cancer (PMID: 30032850 (2018)). Functional evidence suggests that this variant may impact protein function (PMIDs: 33609447 (2022), 33293522 (2020), 29394989 (2018), 29988080 (2018), 24323938 (2014), 23108138 (2013), 18451181 (2008)). The frequency of this variant in the general population, 0.000008 (2/251430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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 pathogenic. -

Jul 22, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 10, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

May 14, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8350C>T (p.R2784W) alteration is located in exon 19 (coding exon 18) of the BRCA2 gene. This alteration results from a C to T substitution at nucleotide position 8350, causing the arginine (R) at amino acid position 2784 to be replaced by a tryptophan (W). 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. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251430) total alleles studied. The highest observed frequency was 0.005% (1/18392) of East Asian alleles. This variant was identified in several breast and ovarian cancer cohorts and segregates with disease (van der Hout, 2006; Gómez García, 2009; Kraus, 2017; Ambry internal data). This alteration was also observed in trans with a pathogenic BRCA2 variant in a patient with Fanconi Anemia (personal communication). Internal structural analysis indicates that this variant is likely to disrupt BRCA2 binding to DSS1, a protein that has been shown to stabilize BRCA2 and participate in its clinically relevant functions (Ambry internal data; Yang, 2002). Several independent assays find this variant non-functional including multiple homology-directed DNA repair assays; a centriole amplification assay and a mouse embryonic stem cell complementation assay (Farrugia, 2008; Guidugli, 2013; Guidugli, 2018; Mesman, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

Jan 07, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 2784 in the DNA binding domain of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown the mutant protein to be non-functional in homology-directed DNA repair activity (PMID: 18451181, 29394989, 29988080, 33609447, 35736817) and unable to complement BRCA2-deficiency in mouse embryonic stem cells (PMID: 29988080). This variant has been observed in over ten individuals and families affected with breast and ovarian cancer (PMID: 18451181, 16683254, 19200354, 21638052, 27153395, 31409081, 31843900, 31742824) and in individuals affected with early-onset or metastatic prostate cancer with family history of prostate and breast cancer (Color internal data). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 4.501 from log(LR)=0.653310001 for 15 carriers (PMID: 31853058). In addition, this variant has been observed in compound heterozygous state with a pathogenic variant in the same gene in at least one individual affected with autosomal recessive Fanconi anemia (FA), indicating that this variant contributes to disease (PMID: 21520333, 34687993; ClinVar variation ID: SCV000186727.6, SCV000073500.12, external communication). This variant has been described as hypomorphic in a FA case (PMID: 34687993). This variant has been identified in 2/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 17, 2022

Sema4, Sema4

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Oct 10, 2018

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

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). -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro 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. -

Nov 24, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breast and/or ovarian cancer

Pathogenic:1

Jun 28, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA2-related cancer predisposition

Pathogenic:1

Jun 25, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRCA2-related disorder

Pathogenic:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRCA2 c.8350C>T variant is predicted to result in the amino acid substitution p.Arg2784Trp. This variant has been reported in an individual with triple-negative breast cancer (Table S4, Kraus et al. 2017. PubMed ID: 27616075), multiple families with a history of hereditary breast and/or ovarian cancer (HBOC) (van der Hout et al. 2006. PubMed ID: 16683254; Gómez García et al. 2009. PubMed ID: 19200354; Table S3, Casadei et al. 2019. PubMed ID: 31843900; Table S2, Shao et al. 2020. PubMed ID: 31742824), and in a non-smoking woman with lung adenocarcinoma (Donner et al. 2018. PubMed ID: 30032850). It has also been observed in an ovarian tumor (Additional file 4, Da Costa et al. 2019. PubMed ID: 31060523). Experimental studies have demonstrated that this variant reduces homology-directed DNA repair (HRD) (Table 2, Guidugli et al. 2013. PubMed ID: 23108138; Farrugia et al. 2008. PubMed ID: 18451181; Guidugli et al. 2018. PubMed ID: 29394989; Mesman et al. 2019. PubMed ID: 29988080). Recent studies have interpreted this variant as pathogenic based on HRD assay results (Hart et al. 2019. PubMed ID: 29884841). This variant has been reported in the gnomAD public population database in 2 of ~251,000 alleles and is interpreted as likely pathogenic by the vast majority of clinical laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38155/). In summary, this variant is interpreted as likely pathogenic. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3+PS4_Moderate -

Familial cancer of breast

Pathogenic:1

Dec 17, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chordoma

Uncertain:1

Mar 22, 2021

Integrative Tumor Epidemiology Branch, National Institutes of Health

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Reduced ES cell viability and drug hypersensitivity (severe impact on BRCA2 function) PMID: 33293522 -

Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Sep 01, 2019

King Laboratory, University of Washington

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:research

This variant yielded normal BRCA2 splicing when tested on RNA from a patientâ€™s lymphoblast cell line using cBROCA. cBROCA evaluates changes in splicing due to germline mutations from participants' RNA and does not evaluate changes that alter function at the protein level. This variant might have an effect at the protein level. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

0.75

PhyloP100

4.3

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.67

MVP

0.96

MPC

0.17

ClinPred

1.0

GERP RS

4.5

gMVP

0.86

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over