Submissions for variant NM_000059.4(BRCA2):c.5946del (p.Ser1982fs) (rs80359550)

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)	RCV000009910	SCV000282418	pathogenic	Breast-ovarian cancer, familial 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000034451	SCV000072813	pathogenic	Hereditary breast and ovarian cancer syndrome	2020-01-08	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 11 of the BRCA2 mRNA (c.5946delT), causing a frameshift at codon 1982. This creates a premature translational stop signal (p.Ser1982Argfs*22) and is expected to result in an absent or disrupted protein product. This pathogenic variant is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266), and has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). In the literature, this variant is also known as 6174delT. This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883, 22430266). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000212245	SCV000108631	pathogenic	not provided	2018-11-19	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.5946delT at the cDNA level and p.Ser1982ArgfsX22 (S1982RfsX22) at the protein level and is also known as 6174delT using alternate nomenclature. The normal sequence with the base that is deleted in brackets is CAAG[delT]GGAA. The deletion causes a frameshift, changing a Serine to an Arginine at codon 1982, and creating a premature stop codon at position 22 of the new reading frame. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. BRCA2 c.5946delT is known to be a pathogenic founder variant in the Ashkenazi Jewish population (Oddoux 1996).
Counsyl	RCV000009910	SCV000154098	pathogenic	Breast-ovarian cancer, familial 2	2014-04-07	criteria provided, single submitter	literature only
Ambry Genetics	RCV000129627	SCV000184420	pathogenic	Hereditary cancer-predisposing syndrome	2018-09-20	criteria provided, single submitter	clinical testing	The c.5946delT pathogenic mutation is located in coding exon 10 of the BRCA2 gene and is one of the well-described Ashkenazi Jewish founder mutations. This mutation results from a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon (p.S1982Rfs*22). This mutation has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu I et al. Clin. Cancer Res. 2009 Feb;15:1112-20; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Lucas AL et al. Clin. Cancer Res. 2013 Jul;19:3396-403; Salo-Mullen EE et al. Cancer. 2015 Dec;121:4382-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Another study indicated that carriers of the c.5946delT mutation may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 mutations (Finkelman BS et al. J. Clin. Oncol. 2012 Apr;30:1321-8). This mutation is also designated as 6174delT 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.
Michigan Medical Genetics Laboratories,University of Michigan	RCV000009910	SCV000195993	pathogenic	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000768632	SCV000219371	pathogenic	Breast and/or ovarian cancer	2017-10-19	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000212245	SCV000225181	pathogenic	not provided	2017-02-03	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000129627	SCV000292121	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212245	SCV000296747	pathogenic	not provided	2019-03-30	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000009910	SCV000327312	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000367838	SCV000383728	pathogenic	BRCA2-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a well-described founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, with a carrier frequency of ~1.5% (Roa et al. 1996; Neuhausen et al. 1996). The variant has been shown to occur in approximately eight percent of women diagnosed with breast cancer before the age of 42 years (Neuhausen et al. 1996; Oddoux et al. 1996; Petrucelli et al. 2010; Finkelman et al. 2012). By the age of 70, 43% of individuals who carry this variant are predicted to develop breast cancer and 20% are predicted to develop ovarian cancer (Struewing et al. 1997; King et al. 2003). Across a selection of the literature, the p.Ser1982ArgfsTer22 variant has been identified in 55 of 1,272 (4%) individuals with breast cancer, 44 of 382 (11.5%) individuals with ovarian cancer, and at least 118 of 9,658 (1.2%) Ashkenazi Jewish individuals from the general population (Couch et al. 1996; Roa et al. 1996; Neuhausen et al. 1996; Oddoux et al. 1996; Struewing et al. 1997; Satagopan et al. 2002; King et al. 2003). Additionally, the p.Ser1982ArgfsTer22 variant has been identified in a compound heterozygous state in four individuals, including two cousins, with Fanconi anemia and brain tumors from three different Ashkenazi Jewish families (Offit et al. 2003; Alter et al. 2007). The p.Ser1982ArgfsTer22 variant was absent from at least 1,726 non-Ashkenazi Jewish controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated decreased cell viability and survival in carriers of the p.Ser1982ArgfsTer22 variant (Wu et al. 2005). The variant protein was shown to be localized in the cytoplasm and not in the nucleus. The p.Ser1982ArgfsTer22 variant is predicted to result in truncation of approximately 41% of the BRCA2 protein, which would remove two signals required for nuclear localization and represents a likely mode of pathogenicity for the variant (Spain et al. 1999). In a study in mouse embryonic stem cells, the p.Ser1982ArgfsTer22 variant failed to rescue the loss of endogenous BRCA2 (Kuznetsov et al. 2008). Based on the collective evidence, the p.Ser1982ArgfsTer22 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414179	SCV000492446	pathogenic	Breast neoplasm		criteria provided, single submitter	research
Baylor Genetics	RCV000044800	SCV000540997	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000009910	SCV000575747	pathogenic	Breast-ovarian cancer, familial 2	2016-02-12	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000034451	SCV000592016	pathogenic	Hereditary breast and ovarian cancer syndrome	2015-07-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory,University of Chicago	RCV000009910	SCV000593749	pathogenic	Breast-ovarian cancer, familial 2	2016-05-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000999951	SCV000602754	pathogenic	none provided	2019-11-11	criteria provided, single submitter	clinical testing	The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (also known as 6174delT) creates a frameshift and is predicted to result in a truncated protein or absent transcript. This variant is known to be a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch 1996, Finkelman 2012), and has been associated with hereditary breast and ovarian cancer syndrome (see ClinVar and references therein). References: Link to ClinVar database for BRCA2 c.5946delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/ Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. Finkelman BS et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol. 2012 Apr 20;30(12):1321-8.
Department of Medical Genetics, Oslo University Hospital	RCV000009910	SCV000605651	pathogenic	Breast-ovarian cancer, familial 2	2015-07-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000034451	SCV000605785	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012) and has been identified in >500 individuals of various ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/projects/bic/). It has also been identified in 0.6% (61/10364) of Ashkenazi Jewish and 0.01% (14/128890) of European chromosomes by gnomAD, http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1982 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function BRCA2 is an established disease mechanism for hereditary breast and ovarian cancer (HBOC) syndrome. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282418.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC based upon the predicted impact to the protein and presence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1, PS4_Strong.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C.	RCV000129627	SCV000679720	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000212245	SCV000693574	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid residues. The protein product thus produced is truncated and non-functional. Truncating variants in BRCA2 are known to be pathogenic. In the literature, this variant is also known as 6174delT and is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266). Moreover, it has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883). The mutation database ClinVar contains entries for this variant (Variation ID: 9325).
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000009910	SCV000744479	pathogenic	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000009910	SCV000803796	pathogenic	Breast-ovarian cancer, familial 2	2017-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000212245	SCV000805732	pathogenic	not provided	2016-03-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000034451	SCV000838826	pathogenic	Hereditary breast and ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009910	SCV000839905	pathogenic	Breast-ovarian cancer, familial 2	2017-05-24	criteria provided, single submitter	clinical testing	The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.[leduc, 2017-03-07]
Integrated Genetics/Laboratory Corporation of America	RCV000034451	SCV000918979	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0002765 in 282088 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503) and was predominantly observed in the Ashkenazi Jewish subpopulation. This variant is a well-established Ashkenazi Jewish founder mutation. The variant, c.5946delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Abeliovich_1997, Friedman_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). Multiple ClinVar submissions after 2014 cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000129627	SCV000996186	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-14	criteria provided, single submitter	clinical testing	This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000212245	SCV001450241	pathogenic	not provided	2014-08-07	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000212245	SCV001501475	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
OMIM	RCV000009910	SCV000030127	pathogenic	Breast-ovarian cancer, familial 2	1995-12-21	no assertion criteria provided	literature only
OMIM	RCV000009911	SCV000030132	risk factor	Pancreatic cancer 2	2016-09-12	no assertion criteria provided	literature only
OMIM	RCV000009912	SCV000030133	pathogenic	Fanconi anemia, complementation group D1	2016-09-12	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034451	SCV000043218	pathogenic	Hereditary breast and ovarian cancer syndrome	2012-07-13	no assertion criteria provided	research	Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000009910	SCV000054198	pathogenic	Breast-ovarian cancer, familial 2	2013-01-15	no assertion criteria provided	clinical testing
GeneReviews	RCV000044800	SCV000086654	pathologic	Familial cancer of breast	2013-09-26	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000009910	SCV000146737	pathogenic	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000009910	SCV000189906	pathogenic	Breast-ovarian cancer, familial 2	2014-07-24	no assertion criteria provided	clinical testing
Curoverse	RCV000034451	SCV000245334	pathogenic	Hereditary breast and ovarian cancer syndrome	2015-08-01	no assertion criteria provided	research	Frameshifts in BRCA2 are considered pathogenic, and this is a BRCA2 Ser1982Arg frameshift variant in exon 11
Centro de Genética y Biología Molecular, Universidad de San Martín de Porres	RCV000009910	SCV000263344	pathogenic	Breast-ovarian cancer, familial 2	2015-06-10	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare	RCV000044800	SCV000484936	pathogenic	Familial cancer of breast		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000034451	SCV000587812	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000009910	SCV000733276	pathogenic	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000212245	SCV000778694	pathogenic	not provided	2017-01-27	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000129627	SCV000787938	pathogenic	Hereditary cancer-predisposing syndrome	2017-09-27	no assertion criteria provided	clinical testing
Gharavi Laboratory,Columbia University	RCV000212245	SCV000809465	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785226	SCV000923794	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research