Submissions for variant NM_000059.4(BRCA2):c.5073dup (p.Trp1692fs)

dbSNP: rs80359479

Total submissions: 48

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031524	SCV000282397	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044550	SCV000072563	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	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.
Ambry Genetics	RCV000130743	SCV000185634	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	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.
GeneDx	RCV000160294	SCV000210759	pathogenic	not provided	2020-01-29	criteria provided, single submitter	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)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768597	SCV000219346	pathogenic	Breast and/or ovarian cancer	2022-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000031524	SCV000220690	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-09-11	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044550	SCV000271329	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000130743	SCV000292169	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-28	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160294	SCV000296735	pathogenic	not provided	2023-07-12	criteria provided, single submitter	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.
GeneKor MSA	RCV000160294	SCV000296824	pathogenic	not provided	2020-01-01	criteria provided, single submitter	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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031524	SCV000327126	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000031524	SCV000593745	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-11-30	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031524	SCV000605702	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044550	SCV000694826	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-10	criteria provided, single submitter	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031524	SCV000840551	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-07-12	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000160294	SCV001248275	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2:Supporting, PS4:Supporting
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031524	SCV001434850	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-12	criteria provided, single submitter	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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310152	SCV001499730	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160294	SCV001716154	pathogenic	not provided	2020-11-03	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Molecular Endocrinology Laboratory, Christian Medical College	RCV000031524	SCV002004011	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160294	SCV002021464	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160294	SCV002506294	pathogenic	not provided	2022-04-05	criteria provided, single submitter	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000031524	SCV002512263	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-02-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Genetics Program, Instituto Nacional de Cancer	RCV000044550	SCV002515115	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000130743	SCV002533923	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-01	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV002272031	SCV002556664	pathogenic	Familial cancer of breast	2021-11-24	criteria provided, single submitter	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).
MGZ Medical Genetics Center	RCV002272031	SCV002579642	pathogenic	Familial cancer of breast	2022-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482932	SCV002780077	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002272031	SCV003834863	pathogenic	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044550	SCV004014935	pathogenic	Hereditary breast ovarian cancer syndrome	2023-03-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160294	SCV004027430	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV002482932	SCV004121692	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2023-11-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031524	SCV004845762	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031524	SCV005045986	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000160294	SCV005199789	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031524	SCV000054129	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031524	SCV000146530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044550	SCV000587741	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031524	SCV000591938	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	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.
Gharavi Laboratory, Columbia University	RCV000160294	SCV000809446	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000031524	SCV001423223	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	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.
CZECANCA consortium	RCV001391216	SCV001593132	pathogenic	Carcinoma of pancreas	2021-03-04	no assertion criteria provided	case-control
GenomeConnect - Invitae Patient Insights Network	RCV001535642	SCV001749677	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160294	SCV001906275	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000160294	SCV001969070	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000044550	SCV002097628	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	literature only	Founder variant in Amish of Somerset County, Pennsylvania
Laboratory for Genotyping Development, RIKEN	RCV003162271	SCV002758297	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000031524	SCV004243650	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing