Submissions for variant NM_007294.4(BRCA1):c.2037delinsCC (p.Lys679fs)

dbSNP: rs397508932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257195	SCV000323387	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000047690	SCV000075703	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16826315, 24916970). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Lys679Asnfs*4) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000257195	SCV000325217	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509787	SCV000607998	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-28	criteria provided, single submitter	clinical testing	The c.2037delGinsCC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from the deletion of one nucleotide and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.K679Nfs*4). This alteration has been reported in multiple individuals of Portuguese and Brazilian ancestry with personal and family histories of breast and/or ovarian cancer (Peixoto A et al. Fam. Cancer 2006 Jul; 5(4):379-87; Esteves VF et al. Braz. J. Med. Biol. Res. 2009 May; 42(5):453-7; Pinto P et al. Breast Cancer Res Treat, 2016 Sep;159:245-56; Palmero EI et al. Sci Rep, 2018 06;8:9188; Barbosa A et al. Cancers (Basel), 2020 Sep;12:). This alteration has also been identified in multiple large, worldwide studies of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620; Santonocito C et al. Cancers (Basel). 2020 May 19;12(5):1286.). Of note, this alteration is also designated as 2156delGinsCC in the 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.
Mendelics	RCV000047690	SCV000839275	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509787	SCV001348872	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.