rs80359598

Positions:

• chr13-32340836-GACAA-G

Variant summary

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

The NM_000059.4(BRCA2):​c.6486_6489del​(p.Lys2162AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,592,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:35
• Conservation: PhyloP100: 1.93

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]

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 13-32340836-GACAA-G is Pathogenic according to our data. Variant chr13-32340836-GACAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 38048.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340836-GACAA-G is described in Lovd as [Pathogenic]. Variant chr13-32340836-GACAA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6486_6489del	p.Lys2162AsnfsTer5	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	c.6486_6489del	p.Lys2162AsnfsTer5	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 33

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000861 AC: 2 AN: 232332 Hom.: 0 AF XY: 0.00000797 AC XY: 1 AN XY: 125532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000972 AC: 14 AN: 1440272 Hom.: 0 AF XY: 0.0000112 AC XY: 8 AN XY: 715286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000254

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000368

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000905

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152128 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:35

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
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, 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)	Jun 22, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 15, 2022	- -
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	New York Genome Center	Jun 11, 2021	The heterozygous c.6486_6489del (p.Lys2162AsnfsTer5) frameshift variant identified in exon 11 (of 27) of the BRCA2 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in multiple unrelated individuals affected with BRCA2-associated disorders [PMID: 10660329; PMID:12474142; PMID:23479189; PMID:26360800; PMID:29339979]. This variant has also been reported as Pathogenic in ClinVar by multiple independent laboratories (Variation ID: 38048). The variant has 0.00001972 allele frequency in the gnomAD(v3) database (3 out of 152128 heterozygous alleles, no homozygotes) indicating it is not a common benign variant in the populations represented in that database. Based on the available evidence, the heterozygousc.6486_6489del (p.Lys2162AsnfsTer5) frameshift variant identified in the BRCA2 gene is reported as Pathogenic. -
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	clinical testing	Counsyl	May 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 23, 2019	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, this variant has been reported in affected individuals with breast, ovarian and/or prostate cancer in the published literature (PMIDs: 29339979 (2018), 29084914 (2018), 26681312 (2016), 26360800 (2016), 23479189 (2013), 20736950 (2010), and 10969800 (2000)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA2: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 22, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2021	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; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 33587123, 32318955, 26689913, 29625052, 31957001, 31454914, 30322717, 30702160, 28176296, 30078507, 30720243, 28724667, 29084914, 29339979, 11389159, 27376475, 28127413, 27225819, 28291774, 26026974, 26681312, 10660329, 10969800, 16684319, 25371446, 26360800, 25452441, 24145998, 18465347, 23479189, 20736950, 12474142) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2024	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2017	Variant summary: The BRCA2 c.6486_6489delACAA (p.Lys2162Asnfs) variant (alternatively also known as 6714del4 and 6710delACAA) results in deletion of 4 nucleotides from exon 11 of the BRCA2 mRNA, causing a frameshift that creates a premature stop codon. This is predicted to cause a truncated or absent (due to nonsense mediated decay) BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.6591_6592delTG (p.Glu2198fs), c.7069_7070delCT (p.Leu2357fs), etc.) This variant was found in the large and broad control populations from ExAC in 2/ 118868 chromosomes at a frequency of 0.0000168, which does not exceed maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in numerous HBOC patients, including male breast cancer and prostate cancer patients (Plaschke_2000, Bergthorsson_2001, Thomassen_2008, Tommasi_2008, Alsop_2012, de Juan_2015, Nielsen_ 2017) and also in a female patient with pancreatic cancer (Pishvaian_2017). In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this 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 31, 2024	This sequence change creates a premature translational stop signal (p.Lys2162Asnfs*5) 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 (rs770263702, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, male breast cancer, and prostate cancer (PMID: 19949876, 20736950, 23479189, 24145998, 24156927, 25586199, 25896959, 26026974, 26360800, 26681312). This variant is also known as 6710delACAA or 6714delACAA. ClinVar contains an entry for this variant (Variation ID: 38048). 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2019	The p.Lys2162AsnfsX5 variant in BRCA2 has been reported in greater than 30 individuals with BRCA2-associated cancer (de Juan Jimenez 2013, Edwards 2003, Edwards 2010, Labidi-Galy 2018, Li 2018, Nielsen 2016, Sun 2017; Breast Information Core database). It has been identified in 1/26026 South Asian and 1/29656 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38048). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2162 and leads to a premature termination codon 5 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast and ovarian cancer syndrome. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 18, 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 6714delACAA, 6714del4, 6710delACAA and 6710del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in over 10 individuals affected with breast and/or ovarian cancer (PMID: 10978364, 11389159, 18694767, 20104584, 23479189, 24145998, 25371446, 25452441, 25586199, 26026974, 26360800, 26681312, 29084914, 30702160, 33471991; Leiden Open Variation Database DB-ID BRCA2_000162) and is reported as a recurrent mutation in Danish hereditary breast and ovarian cancer families (PMID: 18465347). This variant also has been reported in one individual each affected with pancreatic and prostate cancer (PMID: 10969800, 28291774). This variant has been identified in 2/232332 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2024	The c.6486_6489delACAA (p.K2162Nfs*5) alteration, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides between positions 6486 to 6489, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.001% (2/232332) total alleles studied. The highest observed frequency was 0.004% (1/26026) of South Asian alleles. This alteration has been reported in multiple cohorts of individuals and families with early-onset or familial breast cancer (Bergthorsson, 2001; Thomassen, 2008; de Juan Jiménez, 2013; Sambiasi, 2014; D'Argenio, 2015; Hoyer, 2018; Millan Catalan, 2019; Abdel-Razeq, 2021), as well as patients with prostate, ovarian, and pancreatic cancer diagnoses (Edwards, 2003; Edwards, 2010; Roed Nielsen, 2016; Pishvaian, 2017; Li, 2018). Of note, this alteration is also designated as 6714del4 and 6710delACAA in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 21, 2019

The BRCA2 c.6486_6489delACAA; p.Lys2162fs variant (rs80359598) has been reported in individuals affected with breast (de Juan Jimenez 2013), ovarian (Li 2018, Shi 2017), or prostate cancer (Edwards 2003, Edwards 2010). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 38048), and it is observed on only two chromosomes (2/232332 alleles) in the Genome Aggregation Database. 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: de Juan Jimenez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013; 12(4):767-77. Edwards S et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003; 72(1):1-12. Edwards S et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010; 103(6):918-24. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152. Shi T et al. BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic-related mutations in BRCA1 associated with an increased risk of ovarian cancer. Int J Cancer. 2017 May 1;140(9):2051-2059. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

CZECANCA consortium

Jun 11, 2019

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The BRCA2 c.6486_6489delACAA variant is predicted to result in a frameshift and premature protein termination (p.Lys2162Asnfs*5). This variant has been reported in patients with breast, ovarian, and prostate cancer (reported as 6710delACAA in Edwards et al. 2003. PubMed ID: 12474142; reported as 6486delACAA in Edwards et al. 2010. PubMed ID: 20736950; De Juan Jimenez et al. 2013. PubMed ID: 23479189; Table S2, Labidi-Galy et al. 2018. PubMed ID: 29084914). This variant is reported in 0.0038% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by several submitters to ClinVar, including a ClinGen Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38048/). This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2023

- -

Breast carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Apr 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80359598; hg19: chr13-32914973;