Submissions for variant NM_032043.3(BRIP1):c.1425_1429del (p.Leu475fs)

dbSNP: rs768736851

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576786	SCV000677881	likely pathogenic	Fanconi anemia complementation group J; Neoplasm of ovary	2017-02-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000657382	SCV000779115	likely pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing	This deletion of five nucleotides in BRIP1 is denoted c.1425_1429delAACTT at the cDNA level and p.Leu475PhefsX34 (L475FfsX34) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TCTT[delAACTT]TACA. The deletion causes a frameshift, which changes a Leucine to a Phenylalanine at codon 475 and creates a premature stop codon at position 34 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 evidence, we consider this deletion to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000775422	SCV000909782	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-01	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides in exon 10 of the BRIP1 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 identified in 1/244556 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001063357	SCV001228198	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2019-12-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 487424). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Leu475Phefs*34) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000657382	SCV001480053	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775422	SCV002697392	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-08	criteria provided, single submitter	clinical testing	The c.1425_1429delAACTT variant, located in coding exon 9 of the BRIP1 gene, results from a deletion of 5 nucleotides at nucleotide positions 1425 to 1429, causing a translational frameshift with a predicted alternate stop codon (p.L475Ffs*34). 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.
Myriad Genetics, Inc.	RCV003316750	SCV004019319	pathogenic	Familial cancer of breast	2023-02-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.