chr13-32339421-C-CA

Variant names:

• chr13-32339421-C-CA
• rs80359479
• NM_000059.4:c.5073dupA

Variant summary

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

The NM_000059.4(BRCA2):​c.5073dupA​(p.Trp1692MetfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000371 in 1,589,490 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: 0.000039 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:45 O:3
• Conservation: PhyloP100: -0.0410

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 13-32339421-C-CA is Pathogenic according to our data. Variant chr13-32339421-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 37943.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5073dupA	p.Trp1692MetfsTer3	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.5073dupA	p.Trp1692MetfsTer3	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4704dupA	p.Trp1569MetfsTer3	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5073dupA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151574 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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000173 AC: 4 AN: 230778 Hom.: 0 AF XY: 0.0000239 AC XY: 3 AN XY: 125284

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000389 AC: 56 AN: 1437916 Hom.: 0 Cov.: 45 AF XY: 0.0000421 AC XY: 30 AN XY: 713158

Gnomad4 AFR exome AF: 0.0000624

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000427

Gnomad4 OTH exome AF: 0.0000506

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151574 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74030

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: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:45 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14 Other:1

Jan 03, 2017

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Molecular Endocrinology Laboratory, Christian Medical College

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Trp1692MetfsX3 variant was identified in 10 of 5448 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Laarabi 2011, Lubinski 2004, Risch 2001, Suter 2004, Ottini 2009, de Juan 2015, Fernandes 2016, Hasmad 2016). It was also found as a de novo change in a patient who developed early onset breast cancer with no strong family history of the disease (Marshall 2009). The variant was identified in the following databases: dbSNP (ID: rs80359480) as "With Pathogenic allele", ClinVar (18x, pathogenic including review by expert panel ENIGMA), Clinvitae, COGR (3x, pathogenic), LOVD 3.0 (23x, affects function), BIC Database (29x, pathogenic), and ARUP Laboratories (pathogenic). The variant was also identified by our laboratory in 4 individuals with breast, ovarian, and pancreatic cancer. The variant was not found in Cosmic, MutDB, UMD-LSDB, or the Zhejiang University Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.5073dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1692 and leads to a premature stop codon at position 1694. 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. -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 03, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 11, 2014

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Oct 12, 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.5073dupA (p.Trp1692Metfs*3) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with breast cancer or ovarian cancer (PMID: 11179017, 14559878, 16683254, 26026974, 26641009). This variant has been seen 29 times in the Breast Cancer Information Core (BIC) dataset and is extremely rare in the general population according to the gnomAD. Therefore, this c.5073dupA (p.Trp1692Metfs*3) variant in the BRCA2 gene is classified as pathogenic. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 08-30-2017 by Lab or GTR ID 505849. 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. -

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 -

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

- -

not provided Pathogenic:12

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts one nucleotide in exon 11 of the BRCA2 mRNA (c.5073dupA), causing a frameshift at codon 1692. This creates a premature translational stop signal 3 amino acid residues later p.(Trp1692Metfs*3) and is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as 5301insA, 5302insA, and c.5066_5067insA in the international literature and has been reported in individuals affected with breast and/or ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 11179017, 16683254, 10923033, 22144684, 26787237, 25479140, 14559878). The mutation database ClinVar contains entries for this variant (Variation ID: 37943). -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5073dupA; p.Trp1692MetfsTer3 variant (rs80359479), also known as 5301_5302insA or 5301insA in traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Heramb 2018, Laarabi 2011, Palmero 2018, Wen 2018). This variant has also been reported as a de novo variant in an individual with early onset breast cancer (Marshall 2009), and in an individual with Fanconi anemia who was compound heterozygous with a second pathogenic BRCA2 variant (Offit 2003). The c.5073dupA variant is classified as pathogenic by an expert panel in ClinVar (Variation ID: 37943). This variant causes a frameshift by duplicating 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: Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. Laarabi FZ et al. Genetic testing and first presymptomatic diagnosis in Moroccan families at high risk for breast/ovarian cancer. Oncol Lett. 2011 Mar;2(2):389-393. Marshall M et al. Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet. 2009 Nov;76(5):427-30. Offit K et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51. Palmero EI et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018 Jun 15;8(1):9188. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. -

Jan 29, 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 BRCA2-related cancers and reported to occur de novo in at least one case (Sutter 2004, Marshall 2009, Laarabi 2011, Elalaoui 2013, de Juan 2015); 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; Also known as 5301dupA or 5301insA; This variant is associated with the following publications: (PMID: 25479140, 22866093, 28486781, 11179017, 14973102, 19796187, 26541979, 26026974, 25452441, 26064523, 14559878, 26787237, 26641009, 26681312, 23621226, 28814288, 16683254, 10923033, 22144684, 29555025, 28477318, 28724667, 29339979, 29907814, 26556299, 28993434, 26187060, 28176296, 30702160, 31060517, 31396961, 27741520, 29625052, 26689913, 31447099, 31263571, 32029870, 31948886) -

Jun 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2_moderate, PVS1 -

Mar 09, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 12, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5073dup (p.Trp1692Metfs*3) 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 in individuals with ampullary adenocarcinoma (PMID: 36998040 (2023)), ovarian cancer (PMID: 32850417 (2020)), and breast cancer (PMID: 28486781 (2017), 32365798 (2020)). The frequency of this variant in the general population, 0.000028 (3/107130 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jul 31, 2024

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PVS1, PM2:Supporting, PS4:Supporting -

Jan 11, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:6 Other:1

Aug 10, 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.5073dupA (p.Trp1692Metfs) variant 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.5130_5133delTGTA [p.Tyr1710fs). MutationTaster predicts a damaging outcome for this variant. This variant is absent in 119116 control chromosomes (ExAC). The variant has been found in numerous patients/families with breast and/or ovarian cancer, including a confirmed de novo breast cancer case (Marshall_Clin Genet_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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

- -

Apr 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp1692MetfsX3 variant in BRCA2 has been identified in >30 individuals of various ethnicities with Fanconi anemia or BRCA2-related cancers (Risch 2001, Offit 2003, Van Der Hout 2006, Laarabi 2011, Breast Cancer Information Core database). It has also been identified in 1/8884 Ashkenazi Jewish chromosomes by the Genome Aggregation Consortium (GnomAD, http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1692 and leads to a premature termination codon 3 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 in HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282397.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PS4, PM2. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Amish of Somerset County, Pennsylvania -

Jan 23, 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.Trp1692Metfs*3) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 10923033, 11179017, 14559878, 16683254, 22144684, 25479140, 26787237). This variant is also known as 5301insA, 5302insA, and c.5066_5067insA. ClinVar contains an entry for this variant (Variation ID: 37943). For these reasons, this variant has been classified as Pathogenic. -

Mar 21, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Dec 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 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 is also known as 5301insA, 5302insA, c.5066_5067insA and c.5073insA in the literature. This variant has been detected in over 20 individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 11179017, 11938448, 12181777, 14973102, 15131399, 16683254, 18819001, 19052777, 19796187, 21324516, 21465317, 23977390, 24333842, 24728189, 26026974, 26787237, 27741520, 28486781, 32022259, 33471991), an individual affected with pancreatic cancer (PMID: 25479140) and 2 unaffected carriers (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001899). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 2785.593 from log(LR)=3.444917679 for 26 carriers (PMID: 31853058). This variant also has been observed with another pathogenic BRCA2 mutation in an individual affected with the recessive disease Fanconi anemia (PMID: 14559878). This variant has been identified in 4/230778 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 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5073dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 5073, causing a translational frameshift with a predicted alternate stop codon (p.W1692Mfs*3). This mutation has been described in breast and ovarian cancer families of various ethnicities (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Suter NM et al. Cancer Epidemiol. Biomarkers Prev. 2004 Feb;13:181-9; Marshall M et al. Clin. Genet. 2009 Nov;76:427-30; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Hasmad HN et al. Gynecol. Oncol. 2016 May;141:318-22; Sandoval RL et al. PLoS One. 2021 Mar;16:e0247363). This alteration has also been identified in a pancreatic cancer patient (Grant RC et al. Gastroenterology. 2015 Mar;148:556-64). Of note, this alteration is also designated as 5301insA, 5302insA, and c.5066_5067insA 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. -

Familial cancer of breast Pathogenic:3

Mar 16, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5073dupA variant is classified as Pathogenic (PVS1, PM2) This BRCA2 c.5073dupA variant is located in exon 11/27 and is predicted to cause a shift in the reading frame at codon 1692 (PVS1). The variant is rare in population databases (PM2). The variant has been reported in dbSNP (rs80359479) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 37943). -

Feb 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:2

Nov 13, 2023

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

Jan 28, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of pancreas Pathogenic:1

Mar 04, 2021

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 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 is also known as 5301insA, 5302insA, c.5066_5067insA and c.5073insA in the literature. This variant has been detected in over 20 individuals and families affected with breast, ovarian and fallopian tube cancer (PMID: 11179017, 11938448, 12181777, 14973102, 15131399, 16683254, 18819001, 19052777, 19796187, 21324516, 21465317, 23977390, 24333842, 24728189, 26026974, 26787237, 27741520, 28486781, 32022259, 33471991), an individual affected with pancreatic cancer (PMID: 25479140) and 2 unaffected carriers (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001899). This variant also has been observed with another pathogenic BRCA2 mutation in an individual affected with the recessive disease Fanconi anemia (PMID: 14559878). This variant has been identified in 4/230778 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

- -

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 07-02-2018 by 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: rs80359479; hg19: chr13-32913558;