Submissions for variant NM_007294.4(BRCA1):c.329dup (p.Glu111fs) (rs80357604)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031101	SCV000299442	pathogenic	Breast-ovarian cancer, familial 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000195362	SCV000076145	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-10-07	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 6 of the BRCA1 mRNA (c.329dupA), causing a frameshift at codon 111. This creates a premature translational stop signal (p.Glu111Glyfs*3) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular change has been reported in the literature in individuals with breast and/or ovarian cancer (PMID: 20858050, 22762150, 10644434, 25452441, 15146556, 26577449). This variant is also known as 448insA in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000048132	SCV000210000	pathogenic	not provided	2017-10-09	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in BRCA1 is denoted c.329dupA at the cDNA level and p.Glu111GlyfsX3 (E111GfsX3) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 448dupA or 448insA. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]GGAA. The duplication causes a frameshift which changes a Glutamic Acid to a Glycine at codon 111, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.329dupA was observed in multiple individuals with a personal and family history of breast and/or ovarian cancer (Wagner 1999, Meindl 2002, Reeves 2004, George 2016, Rummel 2017). We consider this variant to be pathogenic.
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031101	SCV000267681	pathogenic	Breast-ovarian cancer, familial 1	2016-04-21	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000239071	SCV000296785	pathogenic	Familial cancer of breast	2016-07-01	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031101	SCV000325604	pathogenic	Breast-ovarian cancer, familial 1	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031101	SCV000489151	pathogenic	Breast-ovarian cancer, familial 1	2016-08-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575183	SCV000665804	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-13	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000048132	SCV000887664	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031101	SCV000053697	pathogenic	Breast-ovarian cancer, familial 1	2012-03-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031101	SCV000145076	pathogenic	Breast-ovarian cancer, familial 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000195362	SCV000587047	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research