Submissions for variant NM_032043.3(BRIP1):c.46del (p.Tyr16fs)

dbSNP: rs876660613

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214696	SCV000278184	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-12	criteria provided, single submitter	clinical testing	The c.46delT pathogenic mutation, located in coding exon 1 of the BRIP1 gene, results from a deletion of one nucleotide at nucleotide position 46, causing a translational frameshift with a predicted alternate stop codon (p.Y16Tfs*13). 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.
Invitae	RCV000696347	SCV000824904	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr16Thrfs*13) 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 variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233747). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000214696	SCV000909472	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 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 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.	RCV003335262	SCV004043357	pathogenic	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335263	SCV004046233	pathogenic	BRIP1-associated familial cancer predisposition		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 2 of 20 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, loss-of-function variants in BRIP1 are an established mechanism of disease (PMID: 16116423, 17033622, 21964575). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.46del (p.Tyr16ThrfsTer13) variant is classified as Pathogenic.
Baylor Genetics	RCV003335262	SCV004217138	likely pathogenic	Familial cancer of breast	2023-04-07	criteria provided, single submitter	clinical testing