rs80359718

Positions:

• chr13-32371042-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8575delC​(p.Gln2859fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000805 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q2859Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 5.71

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32371042-AC-A is Pathogenic according to our data. Variant chr13-32371042-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 38169.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32371042-AC-A is described in Lovd as [Pathogenic]. Variant chr13-32371042-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8575delC	p.Gln2859fs	frameshift_variant	20/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8575delC	p.Gln2859fs	frameshift_variant	20/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8206delC	p.Gln2736fs	frameshift_variant	20/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*633delC		non_coding_transcript_exon_variant	19/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*633delC		3_prime_UTR_variant	19/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251220 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727220

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: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

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, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.8575del (p.Gln2859Lysfs*4) variant in the BRCA2 gene is located on the exon 20 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Gln2859Lysfs*4), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 34680878, 36999648, 34399810, 25685387, 31060593, 32098980). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38169) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/251220). Therefore, the c.8575del (p.Gln2859Lysfs*4) variant of BRCA2 has been classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 14, 2022	PVS1, PM2, PS4 -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 17, 2020	The BRCA2 c.8575del (p.Gln2859Lysfs*4) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 11304778 (2001), 20104584 (2010), and 23704984 (2013)), or prostate cancer (PMID: 27433846 (2016)). The frequency of this variant in the general population, 0.00016 (1/6120 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 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; 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 8803delC; This variant is associated with the following publications: (PMID: 11504767, 30720243, 25685387, 20104584, 10359546, 16760289, 11304778, 18703817, 21324516, 26360800, 26833046, 27083775, 27433846, 31723001, 33087929, 30787465, 32570879, 34308366, 28888541, 34399810, 34887416, 33804961, 31060593, 29446198, 33471991) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Gln2859LysfsX4 variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Martin 2001, Pritchard 2016, Roed Nielsen 2016, BIC database). It was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2859 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38169). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -
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	Jun 27, 2021	Variant summary: BRCA2 c.8575delC (p.Gln2859LysfsX4) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251220 control chromosomes. c.8575delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Gln2859Lysfs*4) 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 present in population databases (rs80359718, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 11304778, 20104584, 23704984, 26360800, 27083775, 27433846). This variant is also known as 8803delC. ClinVar contains an entry for this variant (Variation ID: 38169). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Aug 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 27, 2024	The c.8575delC pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8575, causing a translational frameshift with a predicted alternate stop codon (p.Q2859Kfs*4). This mutation has been reported in several individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. J Natl Cancer Inst, 2006 Dec;98:1694-706; Giannini G et al. Breast Cancer Res. Treat. 2006 Nov;100:83-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Petridis C et al. Breast Cancer Res, 2019 05;21:58; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as an individual with lymphoma (Sprissler R et al. Cancers (Basel), 2020 Jun;12). Of note, this alteration is also designated as 8803delC in published literature. 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	Apr 26, 2023	This variant deletes 1 nucleotide in exon 20 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 individuals affected with breast and/or ovarian cancer (PMID: 11304778, 16847550, 17148771, 18703817, 20104584, 21324516, 23704984, 25395318, 27083775), and prostate cancer (PMID: 27433846). This variant has been identified in 1/251220 chromosomes 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	Genetics and Molecular Pathology, SA Pathology	Jul 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 26, 2024	- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Gln2859LysfsX4 deletion variant was identified in 3 of 4874 proband chromosomes from individuals with breast or ovarian cancer (Borg 2010, Loman 2001, Martin 2001). The variant was also identified in dbSNP (ID: rs80359718) “With pathogenic allele”, HGMD, LOVD, and the BIC database (19X as a variant with clinical importance). The p.Gln2859LysfsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2859 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs80359718; hg19: chr13-32945179;