rs80359352

Variant names:

• chr13-32337160-TAAAC-T
• rs80359351
• NM_000059.4:c.2808_2811delACAA

Variant summary

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

The NM_000059.4(BRCA2):​c.2808_2811delACAA​(p.Ala938ProfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,768 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 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:60 O:2
• Conservation: PhyloP100: 1.84

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 13-32337160-TAAAC-T is Pathogenic according to our data. Variant chr13-32337160-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 9322.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337160-TAAAC-T is described in Lovd as [Pathogenic]. Variant chr13-32337160-TAAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2808_2811delACAA	p.Ala938ProfsTer21	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.2808_2811delACAA	p.Ala938ProfsTer21	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2439_2442delACAA	p.Ala815ProfsTer21	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2808_2811delACAA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00000797 AC: 2 AN: 250852 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135696

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461560 Hom.: 0 AF XY: 0.0000220 AC XY: 16 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

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

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:60 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:20

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000059.4:c.2808_2811del (chr13:32337160) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 04, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 04, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2808_2811delACAA (p.Ala938Profs*21) frameshift variant in BRCA2 is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 8524414, 22144684, 21952622, 22006311, 21324516]. This variant is classified as pathogenic. -

Jun 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 11, 2015

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 2016

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

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2013

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:12

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.2808_2811del (p.Ala938Profs*21) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 12955716 (2003), 21598239 (2012), 28724667 (2017), 32101877 (2019), 33558524 (2021)), prostate cancer (PMID: 21952622 (2011)), and pancreatic cancer (PMID: 34399810 (2021)). The frequency of this variant in the general population, 0.000008 (2/250852 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes four bases from exon 11 of the BRCA2 mRNA (c.2808_2811delACAA), causing a frameshift after codon 938 and the creation of a premature translation stop signal 21 amino acid residues later, p.(Ala938Profs*21). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the international literature in individuals affected with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 21952622, 12955716, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. The mutation database ClinVar contains entries for this variant (Variation ID: 9322). -

Jan 27, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 as a recurrent variant in Western European and Hispanic populations (Wooster 1995, Spitzer 2000, Diez 2003, Salazar 2006, Janavicius 2010); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 11158174, 8524414, 10699917, 12955716, 15876480, 23199084, 33054725, 32132887, 31980526, 32029870, 32854451, 32039725, 31263571, 29176636, 31447099, 32318955, 26689913, 29625052, 27741520, 31921681, 31957001, 31432501, 30199306, 31090900, 30093976, 30322717, 30702160, 30014164, 28111427, 30652428, 30078507, 30720863, 30217213, 29310832, 29161300, 29566657, 29907814, 29752822, 29084914, 29368341, 29339979, 28767289, 28680148, 26556299, 28724667, 28195393, 29335924, 27836010, 26576347, 25085752, 29128982, 28127413, 28985766, 27882536, 28008555, 27425403, 22970155, 12065746, 27286788, 26250392, 25371446, 22034289, 16758124, 25884701, 18702510, 12845657, 19383375, 26541979, 26010302, 20713847, 26740091, 25256238, 24916970, 26026974, 25476495, 24504028, 23929434, 22144684, 21952622, 22006311, 21324516, 20736950, 12142080, 29435039, 29470806, 28993434) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.2808_2811delACAA; Ala938ProfsTer21 variant (rs80359351) is reported in the literature in individuals affected with familial breast, ovarian, and prostate cancers (Edwards 2010, Kote-Jarai 2011, Walsh 2011, Wooster 1995, Zhang 2011), and it has been described as a founder variant in Western Europeans (Caputo 2012). This variant is reported as pathogenic by numerous sources in ClinVar (Variation ID: 9322) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. 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 pathogenic. References: Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2, PS4:Moderate -

Jun 19, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PS4_moderate, PVS1 -

Nov 27, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:6 Other:1

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala938ProfsX21 variant in BRCA2 is a well-established pathogenic variant for hereditary breast and ovarian cancer (HBOC) and is one of the most common germline mutations in non-Ashkenazi Jewish individuals with breast cancer (Gao 2000 PMID: 11030417, Diez 2003 PMID: 12955716, Janavicius 2010 PMID: 23199084, Caputo 2012 PMID: 22144684, Kwong 2012 PMID: 22970155, Infante 2013 PMID: 23929434). This variant has also been identified in one male with prostate cancer and 5 males with breast cancer (Edwards 2010 PMID: 20736950, de Juan 2015 PMID: 26026974). Furthermore, this variant was identified in 2/113374 of European chromosomes by tby gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 9322). The p.Ala938ProfsX21 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 938 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism for HBOC. In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -

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

- -

Aug 07, 2017

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.2808_2811delACAA (p.Ala938Profs) variant (legacy names: 3036del4 and 3036delACAA) results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 120732 control chromosomes from ExAC. This variant is known to be a one of the most common pathogenic variants in non-Ashkenazi Caucasians (Diez_2003, Caputo_2012, Hall_2009, Infante_2013). Several clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as pathogenic. Therefore, this variant is classified as pathogenic. -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala938Profs*21) 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 (rs80359351, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 12955716, 21952622, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. ClinVar contains an entry for this variant (Variation ID: 9322). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:5

May 30, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala938Profs*21) 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 (rs80359351, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 12955716, 21952622, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. ClinVar contains an entry for this variant (Variation ID: 9322). For these reasons, this variant has been classified as Pathogenic. -

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

ACMG Guidelines 2015 criteria The BRCA2 variant p.Ala938Profs is a known pathogenic variant in exon 11in a non-functional domain and in a mutation hotspot region of 23 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant truncates the protein domains after this residue which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.00000797 which is less the threshold 0.0001 for recessive gene BRCA2, and this variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282373.1) (PP5 Pathogenic Supporting). In this study this deleterious variant was found in two patients - a 29 and a 38-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 06, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM5_STR -

Breast and/or ovarian cancer Pathogenic:3

Apr 25, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides 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 is also known as c.2806_2809del, 3034del4 and 3036del4 in the literature. This variant has been reported as a recurrent mutation worldwide in over 100 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 11030418, 11158174, 12955716, 15024741, 21324516, 22006311, 21598239, 22970155, 23469205, 25476495, 26026974, 27257965, 28680148, 28692638, 29339979, 30287823) and a breast cancer case-control meta-analysis has reported this variant in 29/60437 cases and 6/53455 unaffected individuals (OR=4.275, 95%CI 1.775 to 10.298) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001211). This variant also has been reported in individuals affected with prostate cancer (PMID: 20736950, 29368341). This variant has been identified in 2/250852 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. -

Dec 09, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2808_2811delACAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 2808 to 2811, causing a translational frameshift with a predicted alternate stop codon (p.A938Pfs*21). This mutation has been identified in multiple families with breast, ovarian, prostate, and other cancers (Diez O et al. Hum. Mutat. 2003 Oct;22:301-12; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Torres D et al. Sci. Rep. 2017 Jul;7:4713; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Isaacsson Velho P et al. Prostate. 2018 Apr;78:401-407; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9; Solano AR et al. Cancers (Basel), 2021 May;13) and has been reported as a Norwegian founder mutation (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 3036del4 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. -

Oct 12, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Pathogenic:2

Nov 01, 2015

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

BRCA2-related disorder Pathogenic:2

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2808_2811del;p.(Ala938Profs*21) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID:11158174) - PS2. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9322; PMID: 21324516; 28680148; 26026974; 20104584) - PS4. This variant is not present in population databases (rs80359351- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Feb 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.2808_2811delACAA variant is predicted to result in a frameshift and premature protein termination (p.Ala938Profs*21). This variant has been repeatedly reported in patients and families with hereditary breast and ovarian cancer (see for example, Wooster et al. 1995. PubMed ID: 8524414; de Juan et al. 2015. PubMed ID: 26026974; Alemar et al. 2017. PubMed ID: 29161300; Heramb et al. 2018. PubMed ID: 29339979) as well as patients with prostate cancer (Edwards et al. 2010. PubMed ID: 20736950; Kote-Jarai et al. 2011. PubMed ID: 21952622). In ClinVar, it is reported as pathogenic by several laboratories, including the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/9322). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

BRCA2-related cancer predisposition Pathogenic:1

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides 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 is also known as c.2806_2809del, 3034del4 and 3036del4 in the literature. This variant has been reported as a recurrent mutation worldwide in over 100 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 11030418, 11158174, 12955716, 15024741, 21324516, 22006311, 21598239, 22970155, 23469205, 25476495, 26026974, 27257965, 28680148, 28692638, 29339979, 30287823) and a breast cancer case-control meta-analysis has reported this variant in 29/60437 cases and 6/53455 unaffected individuals (OR=4.275, 95%CI 1.775 to 10.298) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001211). This variant also has been reported in individuals affected with prostate cancer (PMID: 20736950, 29368341). This variant has been identified in 2/250852 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. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Uterine corpus cancer Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4_Moderate -

Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Ala938Profs*21 variant was identified in 14 of 7122 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian and prostate cancers, although it was not investigated in controls (Edwards 2010, Caux-Moncoutier 2011, Zhang 2011, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80359351) "With Pathogenic allele", ClinVar (classified pathogenic and reviewed by an expert panel 2016, submitters: Invitae, Counsyl, Ambry Genetics, GeneDx and 29 other submitters), and UMD-LSDB (123X, classified as 5-causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2808_2811del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 938 and leads to a premature stop codon 21 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. -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1

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GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 11-12-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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: rs80359351; hg19: chr13-32911297;