Submissions for variant NM_007294.4(BRCA1):c.2728del (p.Gln910fs)

dbSNP: rs397509005

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241323	SCV000299822	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	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	RCV000241323	SCV000325451	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775165	SCV000909334	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-29	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the BRCA1 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 an individual affected with ovarian cancer (PMID: 31742824) and at least one suspected hereditary breast and ovarian cancer family (PMID: 18403564, 29446198, 32614418). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779884	SCV000916771	likely pathogenic	Hereditary breast ovarian cancer syndrome	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2728delC (p.Gln910LysfsX90) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g., c.2766delA [p.Val923fsX77] and c.2806_2809delGATA [p.Asp936fsX63]). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 245542 control chromosomes, but has been identified in at least 2 HBOC patients reported in the literature (De Leeneer_2011; Michils_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Ambry Genetics	RCV000775165	SCV001177363	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	clinical testing	The c.2728delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2728, causing a translational frameshift with a predicted alternate stop codon (p.Q910Kfs*90). This alteration was 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.