Submissions for variant NM_000059.4(BRCA2):c.6990_6994del (p.Ile2330fs)

dbSNP: rs80359631

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113681	SCV000301118	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	RCV000113681	SCV000327555	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562176	SCV000665418	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The c.6990_6994delTACCT pathogenic mutation, located in coding exon 12 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6990 to 6994, causing a translational frameshift with a predicted alternate stop codon (p.I2330Mfs*8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496646	SCV000919012	pathogenic	Hereditary breast ovarian cancer syndrome	2018-10-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6990_6994delTACCT (p.Ile2330MetfsX8) 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., p.Val2333fsX6, p.Gln2342fsX17, and p.Leu2357fsX2). The variant was absent in 244860 control chromosomes. c.6990_6994delTACCT has been reported in multiple individuals affected with Hereditary Breast and Ovarian Cancer. 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000562176	SCV001353907	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 13 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283935	SCV001469446	pathogenic	not provided	2020-03-05	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 patient with expected phenotype for this gene, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496646	SCV001591770	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2330Metfs*8) 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 high risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 52232). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473391	SCV004212906	pathogenic	Familial cancer of breast	2021-09-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113681	SCV004844341	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-08	criteria provided, single submitter	clinical testing	The c.6990_6994del (p.Ile2330Metfs*8) variant in the BRCA2 gene is located on the exon 13 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Ile2330Metfs*8), resulting in an absent or disrupted protein product. The variant has been reported in individuals with hereditary breast and ovarian cancer syndrome (PMID: 31209999, 29854292). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 52232) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.6990_6994del (p.Ile2330Metfs*8) variant of BRCA2 has been classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113681	SCV000146986	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	RCV000496646	SCV000587874	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research