Submissions for variant NM_032043.3(BRIP1):c.1234_1235del (p.Glu412fs)

dbSNP: rs1064795649

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479248	SCV000571650	likely pathogenic	not provided	2018-01-31	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in BRIP1 is denoted c.1234_1235delGA at the cDNA level and p.Glu412SerfsX9 (E412SfsX9) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACA[GA]AGTT. The deletion causes a frameshift which changes a Glutamic Acid to a Serine at codon 412, and creates a premature stop codon at position 9 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. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Ambry Genetics	RCV000575632	SCV000661540	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The c.1234_1235delGA pathogenic mutation, located in coding exon 8 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 1234 to 1235, causing a translational frameshift with a predicted alternate stop codon (p.E412Sfs*9). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853338	SCV000996198	pathogenic	Ovarian Cancers	2018-09-27	criteria provided, single submitter	clinical testing	This frameshifting variant in exon 9 of 20 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. The p.Glu412SerfsTer9 variant has been classified by two clinical laboratories as likely pathogenic and pathogenic in the ClinVar database (Variation ID: 422238). This variant has not been previously reported in the literature or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.1234_1235delGA (p.Glu412SerfsTer9) variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003335369	SCV004044154	pathogenic	Familial cancer of breast	2023-06-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV003766703	SCV004590575	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-09-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 422238). This sequence change creates a premature translational stop signal (p.Glu412Serfs*9) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 28888541). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000479248	SCV005199044	pathogenic	not provided	2022-10-25	criteria provided, single submitter	clinical testing