13-32363369-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000059.4(BRCA2):c.8167G>C(p.Asp2723His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,046 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2723N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:32U:1

Conservation

PhyloP100: 9.60

Publications

95 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 16 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 21 uncertain in NM_000059.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32363369-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 485412.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 13-32363369-G-C is Pathogenic according to our data. Variant chr13-32363369-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 52515.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8167G>C	p.Asp2723His	missense_variant	Exon 18 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.8167G>C	p.Asp2723His	missense_variant	Exon 18 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7798G>C	p.Asp2600His	missense_variant	Exon 18 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*225G>C		non_coding_transcript_exon_variant	Exon 17 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*225G>C		3_prime_UTR_variant	Exon 17 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:10Uncertain:1

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 24, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS3,PP4_STR,PP1_MOD,PP3 -

Nov 11, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 11, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 08, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with histidine at codon 2723 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 that this variant causes the mislocalization of BRCA2 to the cytoplasm (PMID: 15695382, 18607349, 24013206) and disrupts BRCA2 function, including homology-directed DNA repair activity (PMID: 15695382, 18607349, 19043619, 23108138, 25146914). This variant has been reported in over a dozen individuals affected with breast and/or ovarian cancer (PMID: PMID: 11207042, 23961350, 24052750, 24728189, 33471991; Leiden Open Variation Database DB-ID BRCA2_000290) and with prostate cancer (PMID: 23569316). Multifactorial analyses based on numerous individuals' personal and family history of cancer and tumor pathology have determined this variant to be disease-causing (PMID: 15290653, 16489001, 18451181, 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same codon, p.Asp2723Gly, is known to be pathogenic (Clinvar variation ID: 38141), indicating that arginine at this position is important for BRCA2 function. Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:7

Nov 29, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.8167G>C; p.Asp2723His variant (rs41293511), is reported in the literature in several individuals affected with breast and ovarian cancer (Goldgar 2004, Pages 2001, Wu 2005). Functional analyses of BRCA2 protein carrying this variant demonstrate centrosome amplification and aberrant subcellular localization resulting in defective DNA repair on exposure to gamma irradiation and mitomycin-c (Carvalho 2007, Goldgar 2004, Wu 2005). Furthermore, BRCA2 Asp2723His variant has been shown to interfere with the nuclear localization of RAD51, another key DNA repair protein (Jeyasekharan 2013). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 52515). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.932). Several alternative changes at this amino acid location (p.Asp2723Gly, p.Asp2723Ala, p.Asp2723Val) that are predicted to be pathogenic have also been reported in patients with breast and ovarian cancer (Guidugli 2018). Based on available information, the p.Asp2723His variant is considered to be pathogenic. References: Carvalho MA et al. Functional assays for BRCA1 and BRCA2. Int J Biochem Cell Biol. 2007;39(2):298-310. Goldgar DE et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet. 2004 Oct;75(4):535-44. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. Jeyasekharan AD et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. Pages S et al. Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons. Br J Cancer. 2001 Feb;84(4):482-8. Wu K et al. Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res. 2005 Jan 15;65(2):417-26. -

Feb 28, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with personal and family history of BRCA-related cancers, segregating with disease in at least 10 families (Pages et al., 2001; Goldgar et al., 2004; Mitra et al., 2008; Solano et al., 2012; Song et al., 2014; Shimelis et al., 2017); Published functional studies demonstrate a damaging effect: aberrant cellular localization, inability to rescue cell growth, and defective homology-directed repair activity (Wu et al., 2005; Farrugia et al., 2008; Kuznetsov et al., 2008; Jeyasekharan et al., 2013; Guidugli et al., 2018; Hart et al., 2019); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor et al., 2012); 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 8395G>C; This variant is associated with the following publications: (PMID: 24728189, 15695382, 18451181, 18182994, 25447315, 23961350, 25085752, 11207042, 15026808, 29922827, 28888541, 21702907, 22505045, 24323938, 25146914, 25782689, 24013206, 15290653, 19043619, 23108138, 18607349, 16489001, 27225637, 20223037, 26775038, 28283652, 28324225, 26586665, 28008555, 27550963, 26681312, 28158555, 29394989, 29446198, 29988080, 30322717, 30309722, 31263054, 32444794, 30696104, 34399810, 33609447, 30787465, 28184943, 35736817, 35464868, 12228710, 29884841, 33964450, 21990134, 35665744) -

Dec 06, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In the published literature, this variant has been reported in individuals with breast, ovarian, and prostate cancer (PMIDs: 18182994 (2008), 18451181 (2008), 19043619 (2008), 16489001 (2006)), and to segregate with breast and/or ovarian cancer in multiple families (PMIDs: 16489001 (2006), 15290653 (2004)). In addition, this variant has been reported to have a deleterious effect on BRCA2 protein function in numerous studies (PMIDs: 29394989 (2018), 25146914 (2014), 19043619 (2008), 16978908 (2007), 15695382 (2005)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRCA2: PM1:Strong, PS3, PM2, PP1, PS4:Supporting, BP1 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 22, 2025

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified by standard clinical testing. female patient with breast cancer -

Hereditary breast ovarian cancer syndrome

Pathogenic:7

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2723 of the BRCA2 protein (p.Asp2723His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 11207042, 15290653, 16489001, 23961350, 24728189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52515). 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: 15695382, 18607349, 23108138, 24013206, 25146914). This variant disrupts the p.Asp2723 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21990134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jun 12, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp2723His variant in BRCA2 has been identified in >20 individuals with BRCA2-associated cancers and segregated with disease with multiple individuals from many families (Pages 2001 PMID: 11207042, Goldgar 2004 PMID: 15290653, Chenevix-Trench 2006 PMID: 16489001, Solano 2012 PMID: 23961350, Song 2014 PMID: 24728189). This variant was absent from large population studies. In vitro and in vivo functional studies support an impact on protein function (Chenevix-Trench 2006 PMID: 16489001, Wu 2005 PMID: 15695382, Farrugia 2008 PMID: 18451181, Kuznetsov 2008 PMID: 18607349, Jeyasekharan 2013 PMID: 24013206, Guidugli 2018 PMID: 29394989) and computational prediction tools and conservation analysis are consistent with pathogenicity. Moreover, this variant as well as another variant involving this codon (p.Asp2723Gly) have been classified as pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (SCV000244481.1). Multiple other variants involving this codon have also been identified in individuals with HBOC (ClinVar, HGMD: Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PS3_Supporting, PP1_Moderate, PM2, PM5, PP3. -

Sep 27, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 09, 2016

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The BRCA2 c.8167G>C (p.Asp2723His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was absent in 121762 control chromosomes. This variant is a recurrent pathogenic mutation reported in literature and clinical databases with consistent patient and functional data, including support from multifactorial probability model and reported co-segregation with disease. In addition, several clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Therefore, this variant is classified as Pathogenic. -

Apr 07, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PS3 (strong pathogenic): ENIGMA Table 9; Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:29988080, 33609447, 32444794), PP1 (very strong pathogenic): Goldgar 2004 (PMID: 15290653 Table 2): Cosegregation 13,731 / Co-occurrence 2.0, PP3 (supporting pathogenic): BayesDel no-AF: 0.5796, PP4 (strong pathogenic): LR: 79.25654 (USCS combined LR) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with histidine at codon 2723 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 that this variant causes the mislocalization of BRCA2 to the cytoplasm (PMID: 15695382, 18607349, 24013206) and disrupts BRCA2 function, including homology-directed DNA repair activity (PMID: 15695382, 18607349, 19043619, 23108138, 25146914, 35736817). This variant has been reported in over a dozen individuals affected with breast and/or ovarian cancer (PMID: PMID: 11207042, 23961350, 24052750, 24728189, 33471991; Leiden Open Variation Database DB-ID BRCA2_000290) and with prostate cancer (PMID: 23569316). Multifactorial analyses based on numerous individuals' personal and family history of cancer and tumor pathology have determined this variant to be disease-causing (PMID: 15290653, 16489001, 18451181, 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same codon, p.Asp2723Gly, is known to be pathogenic (Clinvar variation ID: 38141), indicating that arginine at this position is important for BRCA2 function. Based on the available evidence, this variant is classified as Pathogenic. -

Apr 24, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D2723H pathogenic mutation (also known as c.8167G>C), located in coding exon 17 of the BRCA2 gene, results from a G to C substitution at nucleotide position 8167. The aspartic acid at codon 2723 is replaced by histidine, an amino acid with some similar properties. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Goldgar DE et al. Am. J. Hum. Genet. 2004 Oct;75:535-44; Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Tavtigian SV et al. Hum. Mutat. 2008 Nov;29:1342-54; Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). Moreover, functional studies have shown that this alteration affects the DNA repair function of BRCA2 (Wu K et al. Cancer Res. 2005 Jan;65:417-26; Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Kuznetsov SG et al. Nat. Med. 2008 Aug;14:875–881; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102:233-248). Additionally, this alteration has been detected in multiple hereditary breast and ovarian cancer families, including families with male breast cancer (Pages S et al. Br. J. Cancer. 2001 Feb;84:482-8; Goldgar DE et al. Am. J. Hum. Genet. 2004 Oct;75:535-44; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Solano AR et al. Springerplus. 2012 Sep;1:20; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). Of note, this alteration is also designated as 8395G>C in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

Sep 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Pathogenic:1

Jun 29, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Carcinoma of pancreas

Pathogenic:1

Mar 04, 2021

CZECANCA consortium

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

BRCA2-related disorder

Pathogenic:1

Oct 18, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRCA2 c.8167G>C variant is predicted to result in the amino acid substitution p.Asp2723His. This variant has been documented in multiple individuals with breast and ovarian cancer and has been shown to cause defective DNA repair (Goldgar et al. 2004. PubMed ID: 15290653; Karchin et al. 2008. PubMed ID: 19043619; Guidugli et al. 2013. PubMed ID: 23108138; Guidugli et al. 2018. PubMed ID: 29394989). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. It is interpreted as pathogenic in ClinVar, including by the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/52515/). This variant is interpreted as pathogenic. -

Malignant tumor of breast

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Asp2723His variant is identified in the literature in 5 out of 554 proband chromosomes (frequency 0.009) in individuals with breast (male and female), ovarian and prostate cancers, however it is not analyzed in enough control chromosomes to determine the population frequency (0 out of 380, frequency=0) (Chenevix-Trench 2006, Mitra 2008, Pages 2001, Ding 2011). Furthermore, It is listed in dbSNP database as coming from a "clinical source" (ID#: rs41293511) with no frequency information available, and therefore, not informative to assess the frequency of this variant in the general population. The p.Asp2723 residue is conserved in mammals and other species and computational analyses (SIFT, Polyphen2, AlignGVGD) predict deleterious impact on the protein function. In addition, in vitro functional studies shows impaired BRCA2 function (Kuzentsov 2008, Wu 2005, Karchin 2008, Walker 2010, Carvalho_2007) and multifactorial likelihood-ratio models shows higher odds in favor of causality for this variant (Goldgar 2004, Farrugia 2008, Chenevix-Trench 2006). In the UMD database, this variant has been identified as an isolated "pathogenous" variant in 19 individuals with breast or ovarian cancers, increasing the likelihood this variant is clinically important. Other variants at the same location include p.Asp2723Gly (5 times in UMD), p.Asp2723Val (2 times in UMD) and p.Asp2723Glu (1 time). The p.Asp2723Gly has been shown to result in loss of the last 164 nucleotides of exon18, and shown to be deleterious by several studies (Farrugia 2008, Easton 2007, Karchin 2008), increasing the likelihood that an alteration to this residue is pathogenic. In summary, based on the above information, this variant is classified as pathogenic. -

Familial cancer of breast

Pathogenic:1

Mar 12, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

PhyloP100

9.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.93

MutPred

0.95

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.99

MPC

0.17

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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