Submissions for variant NM_000059.4(BRCA2):c.6275_6276del (p.Leu2092fs)

gnomAD frequency: 0.00003  dbSNP: rs11571658

Total submissions: 50

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000009903	SCV000282422	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	RCV000044884	SCV000072897	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.Leu2092Profs*7) 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 (rs11571658, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8524414, 20736950, 21324516, 22006311, 22009639, 23199084). It is commonly reported in individuals of European ancestry (PMID: 23199084). This variant is also known as 6503delTT. ClinVar contains an entry for this variant (Variation ID: 9318). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000009903	SCV000154072	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-02-18	criteria provided, single submitter	literature only
Ambry Genetics	RCV000131029	SCV000185959	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-24	criteria provided, single submitter	clinical testing	The c.6275_6276delTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 2 nucleotides between positions 6275 and 6276, causing a translational frameshift with a predicted alternate stop codon (p.L2092Pfs*7). This mutation has been detected in multiple individuals with breast and/or ovarian cancer (Khitto G et al. Hum. Hered. 2001;52:55-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Bayraktar S et al. Cancer. 2012 Mar;118:1515-22; Higgs JE et al. J. Med. Genet. 2015 Sep;52:642-5; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Wang YA et al. BMC Cancer. 2018 03;18:315). Of note, this alteration is also designated as 6503delTT in some 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	RCV000160300	SCV000210777	pathogenic	not provided	2020-05-04	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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Wooster 1995, Edwards 2010, Walsh 2011, Zhang 2011, Bayraktar 2012, Higgs 2015); Also known as 6503delTT; This variant is associated with the following publications: (PMID: 16644204, 26026974, 20002770, 22460208, 10782928, 17850627, 10090482, 15131399, 28392550, 26295337, 29566657, 30630528, 30267214, 24830819, 26041759, 22009639, 22006311, 21324516, 20736950, 8524414, 26843898, 25330149, 16616110, 21993507, 17636422, 26586665, 25884701, 20104584, 14984974, 24156927, 23479189, 20859677, 11039575, 9585608, 9792861, 11453973, 11359068, 10486320, 16905680, 15689453, 17591843, 9537231, 16079000, 11179017, 27225637, 27356891, 28127413, 28301456, 27836010, 27153395, 25085752, 28918466, 12955716, 12698193, 9585613, 12161611, 10227398, 8896551, 23199084, 11597388, 29335925, 29422015, 29915322, 29909963, 30720243, 30322717, 30093976, 31090900, 30612635, 29945567, 32255556, 29625052, 31447099)
Eurofins Ntd Llc (ga)	RCV000160300	SCV000225153	pathogenic	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131029	SCV000292149	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-03	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 dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 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	RCV000160300	SCV000296690	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	This 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 hereditary breast and ovarian cancer (PMID: 27153395 (2016), 11359068 (2001), 12955716 (2003), 21324516 (2011), 22006311 (2011), 22009639 (2012), 23199084 (2010), 26026974 (2015), 26041759 (2015), 29566657 (2018), 29625052 (2018), 8524414 (1995)), male breast cancer (PMID: 29335925(2018)) and prostate cancer (PMID: 20736950 (2010), 29915322 (2018)). In a large scale breast cancer association study, the variant was observed among the breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000081 (4/49646 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its 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	RCV000009903	SCV000327378	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000009903	SCV000577963	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044884	SCV000586966	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-18	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000044884	SCV000588108	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044884	SCV000694953	pathogenic	Hereditary breast ovarian cancer syndrome	2016-07-22	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.6275_6276delTT (p.Leu2092Profs) 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.p.N2135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120912 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous Br/Ov cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000009903	SCV000744484	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009903	SCV000839912	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-10-12	criteria provided, single submitter	clinical testing	This c.6275_6276del (p.Leu2092Profs*7) variant in exon 11 of the BRCA2 gene is a deletion of 2 nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also known as 6503delTT) has been reported in multiple individuals affected with breast, ovarian, and prostate cancer (PMID: 8524414, 22009639, 21324516, 22006311, 20736950, 23199084). The c.6275_6276del (p.Leu2092Profs*7) variant in BRCA2 gene is classified as pathogenic (Atteeq Rehman 10-12-2017).
Academic Department of Medical Genetics, University of Cambridge	RCV000131029	SCV000992213	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160300	SCV001160127	pathogenic	not provided	2018-11-28	criteria provided, single submitter	clinical testing	The BRCA2 c.6275_6276delTT; p.Leu2092fs variant (rs11571658), also known as 6503delTT in traditional nomenclature, is reported in multiple individuals affected with breast, ovarian, or prostate cancer (Bayraktar 2012, de Juan 2015, Edwards 2010, Walsh 2011, Wooster 1995, Zhang 2011). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 9318), and it is found in the general population with a low overall allele frequency of 0.004% (10/274924 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 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: Bayraktar S et al. Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ. Cancer. 2012 Mar 15;118(6):1515-22. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. 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. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000160300	SCV001248279	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009903	SCV001429107	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-14	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160300	SCV001450151	pathogenic	not provided	2015-06-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160300	SCV001714432	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	PP5, PM2, PS4_moderate, PVS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735583	SCV002043320	pathogenic	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160300	SCV002069182	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000044884	SCV002522175	pathogenic	Hereditary breast ovarian cancer syndrome	2021-08-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160300	SCV002551490	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000009903	SCV002580894	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-07-18	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000009903	SCV004031247	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-07-26	criteria provided, single submitter	clinical testing	The BRCA2 c.6275_6276del (p.Leu2092ProfsTer7) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in several individuals with breast and/or ovarian cancer (PMID: 11359068, 21324516, 22006311, 22009639, 26026974, 26041759, 27153395, 29335925, 29566657). It has a maximum subpopulation frequency of 0.0059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 6503delTT in the literature. In summary, this variant meets criteria to be classified as pathogenic.
Baylor Genetics	RCV003473073	SCV004211838	pathogenic	Familial cancer of breast	2024-03-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000009903	SCV004846729	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	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 dozens of individuals affected with breast and/or ovarian cancer and is a common disease-causing mutation in the European population (PMID: 21324516, 23199084, 23479189, 24156927, 26026974, 29566657). This variant also has been detected in a breast cancer case-control meta-analysis in 30/60463 cases and 5/53461 unaffected individuals with odds ratio of 5.307 (95% CI 2.059 to 13.679) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000156). This variant has been identified in 10/274924 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044884	SCV004848254	pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-08	criteria provided, single submitter	clinical testing	The p.Leu2092ProfsX7 variant in BRCA2 has been reported >100 individuals with BRCA2-associated cancer (Breast Information Core Database (BIC)); Bayraktar 2012, de Juan 2015, Edwards 2010, Fostira 2018, Mijuskovic 2018, Walsh 2011, Wang 2018, Whitworth 2018, Wooster 1995, Zhang 2011). In addition, the p.Leu2080X variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282422.1) and has been suggested to be a European founder mutation (Janavicius 2010). This variant has been identified in 0.005% (6/124234) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org. It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2092 and leads to a premature termination codon 7 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 hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000009903	SCV005046005	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	RCV000160300	SCV005198150	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000009903	SCV005201097	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-08-22	criteria provided, single submitter	clinical testing	Null variant (frame-shift) in gene BRCA2, predicted to cause NMD. Loss-of-function is a known mechanism of disease (PVS1).Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 stars. Strong: LOVD classifies this variant as Pathogenic (PP5). GnomAD genomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2,GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2 (PM2).We observed this variant in a 37-year-old woman with malignant breast cancer and a family history of breast cancer.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003473073	SCV005368166	pathogenic	Familial cancer of breast	2024-10-01	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003473073	SCV005397892	pathogenic	Familial cancer of breast	2024-11-14	criteria provided, single submitter	clinical testing
OMIM	RCV000009903	SCV000030124	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2001-01-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000009903	SCV000054219	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-10-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000009903	SCV000146807	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Pathway Genomics	RCV000009903	SCV000189898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-07-24	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044884	SCV000587833	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000160300	SCV000592039	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000009903	SCV000733279	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735583	SCV000863721	pathogenic	Breast and/or ovarian cancer	2015-08-18	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000160300	SCV001798526	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000160300	SCV001905998	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160300	SCV001958808	pathogenic	not provided		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128122	SCV003804353	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000009903	SCV004243708	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000009903	SCV005061334	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control
PreventionGenetics, part of Exact Sciences	RCV004732540	SCV005354488	pathogenic	BRCA2-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The BRCA2 c.6275_6276delTT variant is predicted to result in a frameshift and premature protein termination (p.Leu2092Profs*7). This variant, also known as c.6503delTT and rs11571658 in the literature, has been reported in individuals with breast and ovarian cancer (see, for example, Bayraktar et al. 2012. PubMed ID: 22009639; Table S1, Carter et al. 2018. PubMed ID: 30322717; de Juan et al. 2015. PubMed ID: 26026974), pancreatic cancer (Young et al. 2018. PubMed ID: 29945567), and prostate cancer (Table S3, Darst et al. 2021. PubMed ID: 32853339).  This variant is reported in 0.0059% of alleles in individuals of Latino descent in gnomAD and is classified as pathogenic in the ClinVar database by several other clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/9318/). Taken together, this variant is classified as pathogenic.