Variant 13-32338803-CA-C details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32338803-CA-C is Pathogenic according to our data. Variant chr13-32338803-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37904.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338803-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32338803-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.4449del	p.Asp1484ThrfsTer2	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.4449del	p.Asp1484ThrfsTer2	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461068

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 01, 2022	The BRCA2:c.4449del variant is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA2:c.4449del is a single nucleotide deletion in exon 11 predicted to encode a frame-shift in translation of the mature mRNA with consequent premature termination of protein synthesis at codon 2 of the frame-shift, or 1485 (BRCA2:p.(Asp1484ThrfsTer2) using NP_000050.3. This is predicted to result in absent BRCA2 protein due to nonsense mediated decay (NMD). If NMD is escaped, this variant is expected to encode a truncated protein. Variants of this type are widely accepted to be pathogenic. This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA2:c.4449del as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. This variant is also reported in the literature as BRCA2 4677delA using legacy nomenclature. BRCA2:c.4449del has been reported in multiple unrelated individuals with breast, prostate, or ovarian cancer (Meindl et al., 2002, PMID:11802209, Borg et al., 2010, PMID:20104584, Weren et al., 2017, PMID:27767231, Maier et al., 2014, PMID:25111659). BRCA2:c.4449del (rs80359448) is absent from population databases and is not on record in FLOSSIES. BRCA2:c.4449del is on record in ClinVar (Variation ID:37904) reported by multiple clinical laboratories without conflict as pathogenic in association with hereditary breast and ovarian cancer syndrome. This variant is listed in HGMD as ‘disease causing mutation’ in association with breast and/or ovarian cancer (Accession:CD021793). -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 19, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast, ovarian or prostate cancer (PMID: 20104584, 25111659, 27767231, 29053726, 33471991; Leiden Open Variation Database DB-ID BRCA2_001679; Color internal data), in several suspected hereditary breast and ovarian cancer families (PMID: 11802209, 16683254, 29446198), and in one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001679). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	The BRCA2 c.4449del; p.Asp1484ThrfsTer2 variant (rs80359448), also known as 4677delA, is reported in the literature in multiple individuals and families affected with breast, ovarian, or prostate cancer (Harter 2017, Maier 2014, Meindl 2002, Vos 2019, Weren 2017). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Harter P et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One. 2017 Oct 20;12(10):e0186043. PMID: 29053726. Maier C et al. Subgroups of familial and aggressive prostate cancer with considerable frequencies of BRCA2 mutations. Prostate. 2014 Oct;74(14):1444-51. PMID: 25111659. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. PMID: 11802209. Vos JR et al. Universal tumor DNA BRCA1/2 testing of ovarian cancer: prescreening PARPi treatment and genetic predisposition. J Natl Cancer Inst. 2019 May 11. pii: djz080. PMID: 31076742. Weren RD et al. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. Hum Mutat. 2017 Feb;38(2):226-235. PMID: 27767231. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	BRCA2: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2019	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition it has been reported in individuals affected with ovarian cancer, prostate cancer, and breast cancer in the published literature (PMID: 27767231 (2017), 25111659 (2014), 20104584 (2010), 15744030 (2005)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 11802209, 15744030, 20104584, 25111659, 27767231, 34326862); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 4677delA; This variant is associated with the following publications: (PMID: 16683254, 17403394, 24285858, 32073954, 11802209, 25111659, 18403564, 26681312, 21305653, 27226433, 20104584, 15744030, 15131399, 16684319, 27767231, 28873162, 29791287, 31589614, 28888541, 31076742, 33287145, 29053726, 29446198, 34326862, 34242281, 33471991, 37732318, 37506692) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2022	The c.4449delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4449, causing a translational frameshift with a predicted alternate stop codon (p.D1484Tfs*2). This mutation has been reported in multiple familial breast, ovarian, and prostate cancer kindreds to date (Meindl A et al. Int. J. Cancer 2002 Feb;97:472-80; Leegte B et al. J. Med. Genet. 2005 Mar;42:e20; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Maier C et al. Prostate 2014 Oct;74:1444-51; Weren RD et al. Hum. Mutat. 2017 Feb;38(2):226-235). Of note, this alteration is also designated as 4677delA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2023	This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast, ovarian or prostate cancer (PMID: 20104584, 25111659, 27767231, 29053726, 33471991; Leiden Open Variation Database DB-ID BRCA2_001679; Color internal data), in several suspected hereditary breast and ovarian cancer families (PMID: 11802209, 16683254, 29446198), and in one unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001679). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Familial cancer of breast

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 30, 2024	Criteria applied: PVS1,PM5_STR,PM2_SUP -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Asp1484Thrfs2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is also known as c.4677delA, 1485 and T1483fs. ClinVar contains an entry for this variant (Variation ID: 37904). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

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Calibrated prediction

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Splicing

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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

LitVar

Below is the list of publications found by LitVar. It may be empty.

13-32338803-CA-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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