Submissions for variant NM_000059.4(BRCA2):c.6643del (p.Tyr2215fs)

dbSNP: rs80359614

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077380	SCV000301082	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077380	SCV000327482	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486817	SCV000565684	pathogenic	not provided	2018-01-26	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA2 is denoted c.6643delT at the cDNA level and p.Tyr2215ThrfsX14 (Y2215TfsX14) at the protein level. The normal sequence, with the base that is deleted in braces, is TACT[T]ACTC. The deletion causes a frameshift which changes a Tyrosine to a Threonine at codon 2215, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.6643delT, also known as 6871delT and 6870delT using alternate nomenclature, has been identified in at least two Hereditary Breast and Ovarian Cancer families (Lubinski 2004, Holter 2015). We consider this variant to be pathogenic.
Ambry Genetics	RCV000574731	SCV000668695	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	The c.6643delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6643, causing a translational frameshift with a predicted alternate stop codon (p.Y2215Tfs*14). This mutation has been found in multiple families with hereditary breast, ovarian, and/or pancreatic cancer (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; Copson ER et al. Lancet Oncol., 2018 02;19:169-180). Of note, this alteration is also designated as 6870delT 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.
Color Diagnostics, LLC DBA Color Health	RCV000574731	SCV000683793	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 reported in individuals affected with breast, ovarian, or pancreatic cancer (PMID: 22711857, 25940717, 29337092, Color internal data), and in suspected hereditary breast and ovarian cancer families (PMID: 15131399, 29446198). This variant has been identified in 1/249382 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735589	SCV000901118	likely pathogenic	Breast and/or ovarian cancer	2021-07-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496286	SCV000917024	pathogenic	Hereditary breast ovarian cancer syndrome	2018-09-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6643delT (p.Tyr2215ThrfsX14) 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 4.1e-06 in 244376 control chromosomes (gnomAD). c.6643delT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Holter_2015, Lubinski_2004, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486817	SCV001133868	pathogenic	not provided	2019-05-15	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 not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496286	SCV001578510	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52145). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer and an individual affected with pancreatic adenocarcinoma (PMID: 15131399, 25940717). This variant is present in population databases (rs749364793, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr2215Thrfs*14) 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).
Baylor Genetics	RCV003473384	SCV004211923	pathogenic	Familial cancer of breast	2023-09-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077380	SCV004844289	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide 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 reported in individuals affected with breast, ovarian, or pancreatic cancer (PMID: 22711857, 25940717, 29337092, Color internal data), and in suspected hereditary breast and ovarian cancer families (PMID: 15131399, 29446198). This variant has been identified in 1/249382 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.
Sharing Clinical Reports Project (SCRP)	RCV000077380	SCV000109177	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077380	SCV000146898	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-08-16	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496286	SCV000587861	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000486817	SCV000592067	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Tyr2215ThrfsX14 deletion variant was not identified in the literature but was identified in HGMD and in BIC 2X with clinical importance. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2215 and leads to a premature stop codon 13 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735589	SCV000863727	pathogenic	Breast and/or ovarian cancer	2013-12-11	no assertion criteria provided	clinical testing