Submissions for variant NM_000059.4(BRCA2):c.3847_3848del (p.Val1283fs)

dbSNP: rs80359405

Total submissions: 51

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031440	SCV000282384	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.
Invitae	RCV000044280	SCV000072293	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val1283Lysfs*2) 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 (rs746229647, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, colorectal, prostate and other cancers (PMID: 8589730, 21324516, 21952622, 23199084, 24814045). It is commonly reported in individuals of Scandanavian ancestry (PMID: 23199084). This variant is also known as 4075delGT. ClinVar contains an entry for this variant (Variation ID: 182328, 37859). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131095	SCV000186025	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing	The c.3847_3848delGT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 3847 to 3848, causing a translational frameshift with a predicted alternate stop codon (p.V1283Kfs*2). This mutation has been detected in numerous families with breast, ovarian, pancreatic, and/or prostate cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Hahn SA et al. J. Natl. Cancer Inst. 2003 Feb;95:214-21; Janaviius R. EPMA J. 2010 Sep;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Meisel C et al. Arch Gynecol Obstet. 2017 May;295:1227-1238; El Ansari FZ et al. BMC Cancer. 2020. Aug 10;20(1):747; Heramb C et al. Hered Cancer Clin Pract. 2018 Jan 10;16:3). This mutation was also reported in one family diagnosed with familial colorectal cancer type X (FCCX) that had no alteration detected in the mismatch repair (MMR) pathway (Garre P et al. Clin. Genet. 2015 Jun;87:582-7). Of note, this alteration is also designated as 4075delGT 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	RCV000160281	SCV000210739	pathogenic	Familial cancer of breast	2014-09-16	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3847_3848delGT at the cDNA level and p.Val1283LysfsX2 (V1283KfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT{delGT}AAGT. The deletion causes a frameshift, which changes a Valine to a Lysine at codon 1283 in exon 11, and creates a premature stop codon at position 2 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.3847_3848delGT, previously reported as 4075delGT, has been reported in association with breast and ovarian cancer (Tavtigian 1996). BRCA2 c.3847_3848delGT is also a common mutation in Norwegian and Danish populations (Janavicius 2010). We therefore consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA,HIRISK-BR-HEREDIC,BR-OV-HEREDIC panel(s).
Counsyl	RCV000031440	SCV000220629	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-08-25	criteria provided, single submitter	literature only
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031440	SCV000267761	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	RCV000044280	SCV000271326	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	clinical testing	The p.Val1283LysfsX2 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Wang 2012 PMID:21643751, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.013% (9/67984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). 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 1283 and leads to a premature termination codon 2 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. Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37859). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505838	SCV000296700	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	The BRCA2 c.3847_3848del (p.Val1283Lysfs*2) 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 multiple individuals and families affected with breast/ovarian cancer (PMIDs: 18489799 (2008), 19016756 (2008), 24156927 (2014), 28324225 (2017), 29752822 (2018), 34657373 (2022)), colorectal cancer (PMID: 29321669 (2018)), pancreatic cancer (PMID: 34399810 (2021)), prostate cancer (PMID: 32853339 (2021)), and rhabdomyosarcoma (PMID: 33372952 (2020)). The frequency of this variant in the general population, 0.000098 (11/112032 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031440	SCV000326923	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000160281	SCV000541010	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031440	SCV000605697	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131095	SCV000683584	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This variant deletes 2 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 has been observed in many individuals and families affected with breast and ovarian cancer (PMID: 8589730, 10790213, 17574839, 18465347, 18489799, 19016756, 19620486, 20104584, 21324516, 22752604, 23479189, 24156927, 24528374, 24728189, 28324225, 29752822, 33471991) and is reported as a common cause of hereditary breast and ovarian cancer in Norwegian and Danish populations (PMID: 23199084). This variant has been identified in 12/235838 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.
GeneKor MSA	RCV000505838	SCV000693565	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This is a deletion of two base pairs from exon 11 of the BRCA2 mRNA (c.3847_3848delGT), causing a frameshift at codon 1283. This creates a novel stop codon 2 amino acid residues later and is expected to result in a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4075delGT in the literature and it has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (PMID 21952622, 21324516, 23199084). It was also shown to segregate with disease in a family with colorectal and other cancers (PMID: 24814045). The mutation database ClinVar contains entries for this variant, where it is listed as pathogenic (Variation ID: 37859).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044280	SCV000694724	pathogenic	Hereditary breast ovarian cancer syndrome	2015-06-22	criteria provided, single submitter	clinical testing	Variant summary: This frameshift variant leads to premature truncation at exon 11. In ExAC, it has been observed at allele frequency of 11/94102 chromosomes. This frequency is lower than the maximal expected allele frequency for a pathogenic BRCA2 variant based on the disease prevalence of HBOC. It has been recurrently observed in patients with HBOC. This supports that the 11 individuals with this variant in ExAC are very likely to represent as subclinical cases and/or reduced penetrance. Multiple labs (via ClinVar) classify the variant as pathogenic. Therefore, based on the variant's nature and location, and population and patient data, this has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000505838	SCV000708829	pathogenic	not provided	2017-05-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000031440	SCV000743291	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-10-10	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031440	SCV000839910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-04	criteria provided, single submitter	clinical testing	The c.3847_3848del (p.Val1283Lysfs*2) variant has been detected in several patients and families with breast and/or ovarian cancer [PMID 8589730, 22752604, 24504028, 22006311, 21324516, sometimes reported as 4075delGT], colorectal cancer [PMID 24814045] and prostate cancer [PMID 21952622]. This variant has been reported in 11 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/13-32912337-CTG-C). This 2 bp deletion is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. This pathogenic variant in the BRCA2 gene is also considered medically actionable [ACMG59, PMID 27854360]
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770721	SCV000902200	pathogenic	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031440	SCV000993558	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-02-21	criteria provided, single submitter	research
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000031440	SCV001132517	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-04-12	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505838	SCV001160398	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	The BRCA2 c.3847_3848del; p.Val1283LysfsTer2 variant (rs80359405), also known as 4075delGT, is published in the medical literature in individuals with several types of cancer and families with HBOC (Borg 2010, Garre 2015, Susswein 2016, Wojcik 2016). This variant is reported in ClinVar (Variation ID: 37859) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is found in the general population with an overall allele frequency of 0.0051% (12/235838 alleles) in the Genome Aggregation Database. This variant deletes two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Garre P et al. BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet. 2015 Jun;87(6):582-7. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Wojcik P et al. Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. Hered Cancer Clin Pract. 2016 Feb 3;14:5.
CeGaT Center for Human Genetics Tuebingen	RCV000505838	SCV001248272	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031440	SCV001429311	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000505838	SCV001446642	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000505838	SCV001449752	pathogenic	not provided	2014-05-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000505838	SCV001716151	pathogenic	not provided	2020-06-29	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000505838	SCV002010376	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000505838	SCV002023574	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131095	SCV002533826	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000505838	SCV002550326	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000031440	SCV002579797	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-12-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496481	SCV002814721	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	2022-03-30	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031440	SCV003932720	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	A known pathogenic mutations was detected in the BRCA2 ( c.3847_3848delGT). This sequence change creates a premature translational stop signal (p.Val1283Lysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs746229647, ExAC 0.02%). This variant has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (PMID: 8589730, 21324516, 23199084, 21952622). It was also shown to segregate with disease in a family with colorectal and other cancers (PMID: 24814045). This variant is also known as 4075delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 37859). ClinVar classifies this variant as Pathogenic, 3 stars (expert panel, 39 submissions), citing 22 articles (33372952, 29752822, 29321669, 28324225, 26681312 and 17 more). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000031440	SCV004101533	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing	The c.3847_3848del (p.Val1283LysfsTer2) frameshift variant in BRCA2 gene has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (Zhang et al., 2011; Janavičius 2010). It was also shown to segregate with disease in a family with colorectal and other cancers (Garre et al., 2015). This variant is reported with the allele frequency (0.005%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Valine 1283, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Val1283LysfsTer2. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (Borg et al., 2010). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004532439	SCV004755008	pathogenic	BRCA2-related disorder	2024-02-21	criteria provided, single submitter	clinical testing	The BRCA2 c.3847_3848delGT variant is predicted to result in a frameshift and premature protein termination (p.Val1283Lysfs*2). This variant, also documented as 4075delGT in the literature, has been reported in individuals with breast and/or ovarian cancer (Tavtigian et al. 1996. PubMed ID: 8589730; Zhang et al. 2011. PubMed ID: 21324516; Janavičius. 2010. PubMed ID: 23199084). This variant was also found to segregate with cancer in a family with colorectal cancer type X and prostate cancer (Garre et al. 2015. PubMed ID: 24814045), and it was reported in an additional individual with a personal and family history of prostate cancer (Kote-Jarai et al. 2011. PubMed ID: 21952622). This variant is reported in 0.0098% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported in the ClinVar database as pathogenic and reviewed by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/37859/). In summary, this variant is interpreted as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000031440	SCV004845232	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-15	criteria provided, single submitter	clinical testing	The c.3847_3848del (p.Val1283Lysfs*2) in the BRCA2 gene is located on the exon 11 and is predicted to result in reading frameshift from the codon 1283 and introduce a premature translation termination codon (p.Val1283Lysfs*2), leading to an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832). This variant was reported in more than 10 unrelated individuals with breast/ovarian/prostate cancer (PMID: 32164353, 29325860, 24814045, 32824581, 33670479, 32778078, 33801055, 32923906). It is one of the frequently observed BRCA2 variants in Caucasian and Jewish populations (PMID: 34022715, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37859). The variant is rare in the general population according to gnomAD (12/235838). Therefore, the c.3847_3848del (p.Val1283Lysfs*2) variant of BRCA2 has been classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031440	SCV005045985	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM2_supporting; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000031440	SCV000054045	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-05-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031440	SCV000146307	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Institute of Human Genetics, Medical University Innsbruck	RCV000031440	SCV000212018	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	RCV000044280	SCV000587682	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354023	SCV000591878	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val1283Lysfs*2 variant was identified in 15 of 4576 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian, or pancreatic cancer (Claes 1999, Claus 2005, Hahn 2003, Lubinski 2004, Risch 2001, Singer 2014, Soegaard 2008, Sugano 2008). The variant was also identified in several databases, including: dbSNP (ID: rs80359405) “With pathogenic allele”, COGR (classified as pathogenic by a clinical laboratory), COSMIC, BIC (64x, classified as pathogenic), ARUP Laboratories BRCA Mutations Database, and ClinVar (classified as pathogenic by Ambry Genetics, Counsyl, GeneDx, Division of Human Genetics Innsbruck – Medical University Innsbruck, Sharing Clinical Reports Project, Invitae, and BIC). The variant was identified in control databases in 1 of 199586 chromosomes at a frequency of 0.000005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 1 of 14726 chromosomes (freq: 0.00007); it was not observed in the South Asian, African, Other, Latino, Ashkenazi Jewish, or Finnish populations. The BRCA2, c.3847_3848delGT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1283 and leads to a premature stop codon at position 1284. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031440	SCV000733250	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785219	SCV000923787	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257549	SCV001434375	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
CZECANCA consortium	RCV000770721	SCV001451849	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535666	SCV001749721	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 06-26-2019 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.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001650852	SCV001870396	pathogenic	Breast carcinoma	2021-09-12	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000505838	SCV001905979	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031440	SCV002588868	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162268	SCV002758421	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research