Submissions for variant NM_000059.4(BRCA2):c.6644_6647del (p.Tyr2215fs)

gnomAD frequency: 0.00001  dbSNP: rs80359616

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031642	SCV000301085	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416517	SCV000073019	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2215Serfs*13) 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 (rs80359616, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150172, 16683254, 21120943, 21324516, 22144684). This variant is also known as 6872del4 or 6872delACTC. ClinVar contains an entry for this variant (Variation ID: 38060). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131027	SCV000185957	pathogenic	Hereditary cancer-predisposing syndrome	2024-04-02	criteria provided, single submitter	clinical testing	The c.6644_6647delACTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6644 to 6647, causing a translational frameshift with a predicted alternate stop codon (p.Y2215Sfs*13). This mutation has been reported in numerous individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Serova-Sinilnikova OM et al. Am. J. Hum. Genet., 1997 May;60:1236-9; Verhoog LC et al. J. Clin. Oncol., 1999 Nov;17:3396-402; Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Lewis CM et al. Breast Cancer Res Treat, 2006 Sep;99:103-15; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34; Caputo S et al. Nucleic Acids Res, 2012 Jan;40:D992-1002; Lecarpentier J et al. Breast Cancer Res, 2012 Jul;14:R99; Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333). This mutation has also been reported in multiple individuals with pancreatic cancer (Huang KL et al. Cell, 2018 04;173:355-370.e14; Hu C et al. JAMA, 2018 06;319:2401-2409). Of note, this alteration is also designated as 6872del4 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	RCV000219562	SCV000278871	pathogenic	not provided	2021-01-19	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 and/or family history of breast and/or ovarian cancer (Serova-Sinilnikova 1997, Verhoog 1999, Risch 2001, Verhoog 2001, Lewis 2006, Zhang 2011, Caputo 2012, Tung 2015, Johnson 2017, Labidi-Galy 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6872_6875delACTC; This variant is associated with the following publications: (PMID: 11179017, 29625052, 9150172, 16683254, 21324516, 22144684, 26586665, 26926684, 16541310, 22019625, 11597388, 21120943, 25186627, 28526081, 28476184, 15131399, 29084914, 10550133, 30720243)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031642	SCV000327483	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416517	SCV000494433	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, BRCA2 c.6644_6647delACTC (p.Tyr2215SerfsX13) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.6682dupG(p.Val2228fsX5), c.6757_6758delCT(p.Leu2253fsX7)). The variant allele was found at a frequency of 4.1e-06 in 244534 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Caputo_2012, Lee_2008, Hu_2018, Zhang_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000219562	SCV000602786	pathogenic	not provided	2020-05-21	criteria provided, single submitter	clinical testing	The BRCA2 c.6644_6647delACTC; p.Tyr2215fs variant (rs80359616), also known as c.6872del4, is reported in the literature in several individuals with breast and/or ovarian cancer (Caputo 2012, Serova-Sinilnikova 1997, Zhang 2011). This variant is also reported in ClinVar (Variation ID: 38060). It is only observed on one allele 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 to be 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;40(Database issue):D992-1002. Serova-Sinilnikova OM et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997 May;60(5):1236-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121(2):353-7.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000416517	SCV000605813	pathogenic	Hereditary breast ovarian cancer syndrome	2017-01-27	criteria provided, single submitter	clinical testing	The p.Tyr2215fs variant in BRCA2 has been reported in >25 individuals with BRCA2 -associated cancers and segregated with disease in 5 relatives from 2 families ( Serova-Sinilnikova 1997, Caputo 2012, Zhang 2011, Risch 2001, Verhoog 2001, and Breast Cancer Information Core (BIC) database). It was also absent from large po pulation studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2215 and leads to a prem ature termination codon 13 amino acids downstream. This alteration is then predi cted 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 ovar ian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301085 .2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Counsyl	RCV000031642	SCV000677694	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-18	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031642	SCV000744497	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000219562	SCV000889109	pathogenic	not provided	2019-11-26	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been seen in affected individuals with ovarian cancer in the published literature (PMIDs: 21324516 (2011), 22144684 (2012), 29084914 (2018), and 30720243 (2019)). Based on the available information, this variant is classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769701	SCV000901119	pathogenic	Breast and/or ovarian cancer	2017-05-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131027	SCV000911346	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	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 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000219562	SCV001446538	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000219562	SCV001714434	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Sema4, Sema4	RCV000131027	SCV002536253	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
Baylor Genetics	RCV003473205	SCV004211924	pathogenic	Familial cancer of breast	2024-02-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031642	SCV004844290	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	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 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 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 Pathology and Laboratory Medicine, Sinai Health System	RCV005357210	SCV005919941	pathogenic	BRCA2-related cancer predisposition	2021-08-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031642	SCV000054249	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031642	SCV000146900	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000416517	SCV000587863	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000219562	SCV001906438	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031642	SCV004243731	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732574	SCV005360573	pathogenic	BRCA2-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The BRCA2 c.6644_6647delACTC variant is predicted to result in a frameshift and premature protein termination (p.Tyr2215Serfs*13). This variant has been reported in several individuals with breast and ovarian cancer (Serova-Sinilnikova et al. 1997. PubMed ID: 9150172; van der Hout et al. 2006. PubMed ID: 16683254; reported as 6872del4 in Zhang et al. 2011. PubMed ID: 21324516). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as pathogenic by many genetic testing laboratories and the Evidence-based Network for the Interpretation of Germline Mutant Alleles expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38060/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.