Submissions for variant NM_000059.4(BRCA2):c.6682dup (p.Val2228fs)

dbSNP: rs80359621

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113628	SCV000301093	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.
Ambry Genetics	RCV000218189	SCV000273788	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-16	criteria provided, single submitter	clinical testing	The c.6682dupG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of one nucleotide at position 6682, causing a translational frameshift with a predicted alternate stop codon (p.V2228Gfs*5). This duplication has been previously reported in an HBOC family (Lubinski J et al. Fam Cancer. 2004;3:1-10). This alteration was detected in a cohort of women diagnosed with triple-negative breast cancer (Wong-Brown MW et al. Breast Cancer Res Treat. 2015 Feb;150:71-80). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation-positive families (Rebbeck TR et al. Hum Mutat. 2018 05;39:593-620). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113628	SCV000327494	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268512	SCV001447495	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496313	SCV001582296	pathogenic	Hereditary breast ovarian cancer syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15131399, 25682074). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val2228Glyfs*5) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52155). This variant is also known as c.6909insG.
GeneDx	RCV001268512	SCV001793406	pathogenic	not provided	2020-12-28	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 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; Identified in a patient with a personal or family history meriting testing for hereditary breast and ovarian cancer syndrome (Lubinski 2004); Also known as 6909insG or 6910dupG; This variant is associated with the following publications: (PMID: 15131399)
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113628	SCV000146910	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1999-08-27	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496313	SCV000587864	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research