Submissions for variant NM_032043.3(BRIP1):c.1702_1703del (p.Asn568fs)

dbSNP: rs1057519365

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer	RCV000416663	SCV000262602	likely pathogenic	Carcinoma of colon	2015-11-01	criteria provided, single submitter	clinical testing	Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for gastric cancer
GeneDx	RCV000477976	SCV000568501	likely pathogenic	not provided	2016-09-07	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in BRIP1 is denoted c.1702_1703delAA at the cDNA level and p.Asn568TrpfsX9 (N568WfsX9) at the protein level. The normal sequence, with the bases that are deleted in braces, is CAAA[AA]TGGG. The deletion causes a frameshift which changes an Asparagine to a Tryptophan at codon 568, and creates a premature stop codon at position 9 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. BRIP1 c.1702_1703delAA has been observed in individuals with ovarian, breast and colorectal cancer (Rafnar 2011, Esteban-Jurado 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Ambry Genetics	RCV000570267	SCV000661490	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-14	criteria provided, single submitter	clinical testing	The c.1702_1703delAA pathogenic mutation, located in coding exon 11 of the BRIP1 gene, results from a deletion of two nucleotides at nucleotide positions 1702 to 1703, causing a translational frameshift with a predicted alternate stop codon (p.N568Wfs*9). In one study, this mutation was reported in 2/144 Spanish individuals with ovarian cancer, 6/927 Spanish individuals with breast cancer, and 1/1780 controls (Rafnar T et al. Nat. Genet. 2011 Nov; 43(11):1104-7). This alteration was also reported in Spanish male diagnosed with colon cancer at age 80 who had a family history of colon, stomach, and bladder cancer (Esteban-Jurado C et al. Genet. Med. 2015 Feb; 17(2):131-42; Esteban-Jurado C et al. Eur. J. Hum. Genet. 2016 Oct;24:1501-5) and in an individual diagnosed with breast cancer at 32 (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). 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.
Color Diagnostics, LLC DBA Color Health	RCV000570267	SCV000684152	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 12 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 reported in two individuals affected with ovarian cancer (PMID: 21964575) and eight individuals affected with breast cancer (PMID: 21964575, 30306255, 31786208), as well as in an individual with colorectal cancer (PMID: 27165003). This variant has been identified in 1/251398 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636137	SCV000757569	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn568Trpfs*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 present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and ovarian cancer (PMID: 21964575, 25058500). ClinVar contains an entry for this variant (Variation ID: 221621). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000663330	SCV000786604	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	2018-06-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000636137	SCV002800298	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2021-07-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316152	SCV004019326	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.
Baylor Genetics	RCV003316152	SCV004214656	pathogenic	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing