Variant rs80359538 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 13-32340151-TAACC-T is Pathogenic according to our data. Variant chr13-32340151-TAACC-T is described in ClinVar as [Pathogenic]. Clinvar id is 37998.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340151-TAACC-T is described in Lovd as [Pathogenic]. Variant chr13-32340151-TAACC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5799_5802del	p.Asn1933LysfsTer29	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.5799_5802del	p.Asn1933LysfsTer29	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 06, 2021	The BRCA2 c.5799_5802del, p.Asn1933LysfsTer29 variant, also known as 6027del4 in alternative nomenclature, is reported in the literature in several individuals with a personal and/or family history of breast cancer (PMID: 22682623, 28008555). This variant is absent from the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. This variant causes a frameshift by deleting four nucleotides, which is predicted to result in atruncated protein or mRNA subject to nonsense-mediated decay. Based on the available evidence, c.5799_5802del, p.Asn1933LysfsTer29 variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 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, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2015	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 24, 2020	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast, ovarian, anal, and uterine cancer in the published literature (PMID: 26556299 (2016), 26681312 (2015), 22682623 (2012), 15131399 (2004)). Based on available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	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: 22682623, 28495237, 28008555); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6027_6030delCCAA or 6027del4; This variant is associated with the following publications: (PMID: 22109874, 31794323, 34413315, 28888541, 15131399, 22682623, 26681312, 28008555, 28127413, 28495237, 26556299, 30787465, 31892343, 30322717, 26221963, 30068706, 29263802, 29308099) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 24, 2019	The BRCA2 c.5799_5802delCCAA; p.Asn1933fs variant (rs80359538), also known as 6027del4 in alternative nomenclature, is reported in the literature in several individuals with a personal and/or family history of breast cancer (Dutil 2012, Pritzlaff 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37998). This variant causes a frameshift by deleting four nucleotides, 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: Dutil J et al. Identification of the prevalent BRCA1 and BRCA2 mutations in the female population of Puerto Rico. Cancer Genet. 2012 May;205(5):242-8. Pritzlaff M et al. Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat. 2017 Feb;161(3):575-586. -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 05, 2022	The c.5799_5802delCCAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5799 to 5802, causing a translational frameshift with a predicted alternate stop codon (p.N1933Kfs*29). This mutation has been reported in multiple breast and/or ovarian cancer families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Dutil J et al. Cancer Genet. 2012 May;205:242-8; Wong E et al. Genomic Medicine. 2016 Jan;1:15003; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). Of note, this alteration is also designated as 6027del4 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	Nov 13, 2023	This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 6072del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in several individuals affected with breast or ovarian cancer (PMID: 22682623, 26221963, 28008555, 29263802, 29308099, 30322717). This variant has also been reported in six suspected hereditary breast and ovarian cancer families (PMID: 15131399, 29446198). 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. -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change creates a premature translational stop signal (p.Asn1933Lysfs*29) 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 premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 15131399, 22682623, 26681312, 28008555). This variant is also known as 6027del4. ClinVar contains an entry for this variant (Variation ID: 37998). 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: BRCA2 c.5799_5802delCCAA (p.Asn1933LysfsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Other truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245780 control chromosomes. c.5799_5802delCCAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

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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.

rs80359538

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation