Submissions for variant NM_032043.3(BRIP1):c.1941G>A (p.Trp647Ter)

dbSNP: rs786202760

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000565890	SCV000673150	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	The p.W647* pathogenic mutation (also known as c.1941G>A), located in coding exon 13 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1941. This changes the amino acid from a tryptophan to a stop codon within coding exon 13. 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.
GeneDx	RCV000657705	SCV000779454	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28888541, 32359370)
Invitae	RCV000690470	SCV000818156	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2023-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 485455). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp647*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526941	SCV001737710	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-30	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1941G>A (p.Trp647X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251268 control chromosomes. c.1941G>A has been reported in the literature in at-least one individual affected with Ovarian Cancer in a recent large scale meta-analysis based on a comparison of a total of approximately 29,400 ovarian cancer patients from 63 studies and a total of approximately 116,000 controls (Suszynska_2020). This large study provides stronger evidence for the pathogenic role of BRIP1 along with RAD51C and RAD51D mutations in Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001783077	SCV002017984	pathogenic	Fanconi anemia complementation group J	2019-02-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003335517	SCV004043553	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.
Baylor Genetics	RCV003335517	SCV004214773	pathogenic	Familial cancer of breast	2023-09-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565890	SCV004362923	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 14 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 32359370). 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.