Submissions for variant NM_007294.4(BRCA1):c.2213_2214dup (p.Lys739fs) (rs80357574)

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Total submissions: 6

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031038	SCV000323426	pathogenic	Breast-ovarian cancer, familial 1	2016-10-18	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000167068	SCV000217896	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031038	SCV000325294	pathogenic	Breast-ovarian cancer, familial 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657536	SCV000779272	pathogenic	not provided	2018-05-03	criteria provided, single submitter	clinical testing	This duplication of two nucleotides in BRCA1 is denoted c.2213_2214dupTT at the cDNA level and p.Lys739LeufsX15 (K739LfsX15) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 2214_2215dupTT or 2332_2333dupTT. The normal sequence, with the bases that are duplicated in brackets, is ACAG[dupTT]AAAG. The duplication causes a frameshift, which changes a Lysine to a Leucine at codon 739 and creates a premature stop codon at position 15 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Invitae	RCV001048511	SCV001212522	pathogenic	Hereditary breast and ovarian cancer syndrome	2019-03-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys739Leufs*15) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family at increased risk of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 37457). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031038	SCV000053632	pathogenic	Breast-ovarian cancer, familial 1	2012-05-10	no assertion criteria provided	clinical testing

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