Submissions for variant NM_000059.3(BRCA2):c.2808_2811del (p.Ala938Profs)

dbSNP: rs80359351

Total submissions: 62

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000009907	SCV000282373	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	RCV000044064	SCV000072077	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	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.
Ambry Genetics	RCV000131102	SCV000186032	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	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.
GeneDx	RCV000160273	SCV000210725	pathogenic	not provided	2020-01-27	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 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)
Counsyl	RCV000009907	SCV000220481	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-04	criteria provided, single submitter	literature only
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240755	SCV000265905	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210161	SCV000266039	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-11-20	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000009907	SCV000267754	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044064	SCV000271324	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-30	criteria provided, single submitter	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.
Color Diagnostics, LLC DBA Color Health	RCV000131102	SCV000292132	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160273	SCV000296702	pathogenic	not provided	2023-08-03	criteria provided, single submitter	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.
GeneKor MSA	RCV000160273	SCV000296818	pathogenic	not provided	2020-01-01	criteria provided, single submitter	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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000009907	SCV000326768	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000240755	SCV000492474	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Baylor Genetics	RCV000458791	SCV000541011	pathogenic	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000009907	SCV000577950	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000044064	SCV000588085	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000009907	SCV000605665	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044064	SCV000694631	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-07	criteria provided, single submitter	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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009907	SCV000744430	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160273	SCV000778656	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate, PVS1
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009907	SCV000839926	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-22	criteria provided, single submitter	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160273	SCV000885087	pathogenic	not provided	2022-06-22	criteria provided, single submitter	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.
Mendelics	RCV000009907	SCV001139044	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160273	SCV001248268	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000160273	SCV001446776	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000210161	SCV001499721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160273	SCV002010724	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160273	SCV002023674	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735443	SCV002042555	pathogenic	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
DASA	RCV001849261	SCV002107109	pathogenic	BRCA2-related disorder	2022-03-05	criteria provided, single submitter	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.
Genetics Program, Instituto Nacional de Cancer	RCV000044064	SCV002515258	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131102	SCV002535526	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000009907	SCV002579943	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000458791	SCV003926644	pathogenic	Familial cancer of breast	2023-05-30	criteria provided, single submitter	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.
Baylor Genetics	RCV000009907	SCV004041288	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160273	SCV004242916	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000009907	SCV004845059	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-09	criteria provided, single submitter	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000009907	SCV005045984	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	RCV000160273	SCV005199036	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000458791	SCV005368357	pathogenic	Familial cancer of breast	2024-07-24	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795387	SCV005416111	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Moderate
OMIM	RCV000009907	SCV000030128	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1995-12-21	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000009907	SCV000053988	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-07-29	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000009907	SCV000146117	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-02-20	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000009907	SCV000212014	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-02-11	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044064	SCV000587644	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354011	SCV000591826	pathogenic	Malignant tumor of breast		no assertion criteria provided	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.
GenomeConnect, ClinGen	RCV000044064	SCV000607364	not provided	Hereditary breast ovarian cancer syndrome		no assertion provided	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000009907	SCV000733240	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735443	SCV000863579	pathogenic	Breast and/or ovarian cancer	2016-03-29	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000458791	SCV000987243	pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	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.
CZECANCA consortium	RCV000735443	SCV001451798	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160273	SCV001906411	pathogenic	not provided		no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000458791	SCV002520773	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000009907	SCV002588861	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162225	SCV002758329	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
CZECANCA consortium	RCV003128124	SCV003804355	pathogenic	Uterine corpus cancer	2023-02-21	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000009907	SCV004022143	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-21	no assertion criteria provided	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.
GenomeConnect - Invitae Patient Insights Network	RCV003483429	SCV004228769	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	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.
PreventionGenetics, part of Exact Sciences	RCV001849261	SCV004759448	pathogenic	BRCA2-related disorder	2024-02-16	no assertion criteria provided	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.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000009907	SCV005061318	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control