Submissions for variant NM_032043.3(BRIP1):c.1697_1698insTATATCAAATTGATATTTCAACAAC (p.Asp566_Lys567insIleSerAsnTer)

dbSNP: rs878855140

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232677	SCV000290985	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2016-03-11	criteria provided, single submitter	clinical testing	This sequence change inserts 25 nucleotides in exon 12 of the BRIP1 mRNA (c.1697_1698insTATATCAAATTGATATTTCAACAAC), causing a frameshift at codon 567. This creates a premature translational stop signal (p.Lys567Ilefs*4) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483400	SCV000570254	pathogenic	not provided	2017-11-17	criteria provided, single submitter	clinical testing	This insertion of 25 nucleotides in BRIP1 is denoted c.1697_1698ins25 at the cDNA level and p.Lys567IlefsX4 (K567IfsX4) at the protein level. The surrounding sequence is CAGA[ins25]CAAA. The insertion causes a frameshift, which changes a Lysine to an Isoleucine at codon 567 and creates a premature stop codon at position 4 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 insertion to be pathogenic.
Ambry Genetics	RCV000572341	SCV000668972	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The c.1697_1698ins25 variant, located in coding exon 11 of the BRIP1 gene, results from an insertion of 25 nucleotides at position 1697, causing a translational frameshift with a predicted alternate stop codon (p.K567Ifs*4). 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.
Color Diagnostics, LLC DBA Color Health	RCV000572341	SCV000910088	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant is located in the BRIP1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified 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.
Myriad Genetics, Inc.	RCV003335278	SCV004043724	pathogenic	Familial cancer of breast	2023-06-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.