Submissions for variant NM_000059.4(BRCA2):c.6444dup (p.Ile2149fs)

dbSNP: rs80359590

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031628	SCV000301045	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	RCV000044952	SCV000072965	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2149Tyrfs*2) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and pancreatic cancer (PMID: 12569143, 22006311, 22666503, 26681312). This variant is also known as 6672insT. ClinVar contains an entry for this variant (Variation ID: 38046). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000258965	SCV000210780	pathogenic	not provided	2024-04-12	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 significant frequency in large population cohorts (gnomAD); Observed in individuals with BRCA2-related cancers (PMID: 12569143, 22006311, 22666503, 27084275); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6672dupT; This variant is associated with the following publications: (PMID: 26681312, 32295079, 22006311, 22666503, 12569143, 27084275, 22430266, 18437078, 26402249, 32341426, 30787465, 30322717, 20104584, 35710434)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031628	SCV000327429	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563635	SCV000665988	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-13	criteria provided, single submitter	clinical testing	The c.6444dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 6444, causing a translational frameshift with a predicted alternate stop codon (p.I2149Yfs*2). This mutation was detected in an individual diagnosed with pancreatic cancer at age 65 (Hahn SA et al. J. Natl. Cancer Inst. 2003 Feb;95(3):214-21), and in another individual diagnosed with triple negative breast cancer at age 36 and a second breast tumor at age 43 (Meyer P et al. PLoS ONE 2012; 7(5):e38361). Of note, this alteration is also designated as 6672insT 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	RCV000563635	SCV001348956	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant inserts 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 not been identified 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.
Baylor Genetics	RCV003473201	SCV004210456	pathogenic	Familial cancer of breast	2022-11-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803061	SCV005424533	pathogenic	BRCA2-related cancer predisposition	2024-07-10	criteria provided, single submitter	clinical testing	This variant inserts 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 is also known as 6672insT in the literature. This variant has been reported individuals affected with breast and/or ovarian cancer (PMID: 22006311, 22666503, 26681312), and pancreatic cancer (PMID: 12569143). This variant has not been identified 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)	RCV000031628	SCV000054235	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2009-03-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031628	SCV000146854	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000044952	SCV000587847	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
CZECANCA consortium	RCV001271045	SCV001451864	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031628	SCV004243717	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing