Submissions for variant NM_032043.3(BRIP1):c.1776G>A (p.Trp592Ter)

dbSNP: rs753023295

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215063	SCV000279761	likely pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1776G>A at the cDNA level and p.Trp592Ter (W592X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
Ambry Genetics	RCV001013105	SCV001173647	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.W592* pathogenic mutation (also known as c.1776G>A), located in coding exon 11 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1776. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. This alteration was reported in a patient with serous ovarian cancer diagnosed at age 71 and no family history of cancer in first degree relatives (Eoh KJ et al. Cancer Res. Treat. 2018 Jul;50:917-925). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047429	SCV001211390	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp592*) 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: 29020732). ClinVar contains an entry for this variant (Variation ID: 234745). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003335268	SCV004044197	pathogenic	Familial cancer of breast	2023-06-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.