Submissions for variant NM_032043.3(BRIP1):c.2244C>G (p.Tyr748Ter)

dbSNP: rs1257401983

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Yang An-Suei Laboratory, Academia Sinica	RCV000504601	SCV000583424	pathogenic	Breast neoplasm		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000576013	SCV000661520	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The p.Y748* pathogenic mutation (also known as c.2244C>G), located in coding exon 14 of the BRIP1 gene, results from a C to G substitution at nucleotide position 2244. This changes the amino acid from a tyrosine to a stop codon within coding exon 14. This alteration has been previously reported in an individual with primary peritoneal serous carcinoma (Sung PL et al. PLoS ONE, 2017 Sep;12:e0185615). 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.
GeneDx	RCV000657691	SCV000779440	pathogenic	not provided	2021-10-20	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 (Lek 2016); This variant is associated with the following publications: (PMID: 29566657, 28961279, 31742824)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694900	SCV000823366	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.Tyr748*) 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 primary peritoneal serous carcinoma (PMID: 28961279). ClinVar contains an entry for this variant (Variation ID: 430591). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003335408	SCV004044248	pathogenic	Familial cancer of breast	2023-06-06	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492076	SCV004240392	likely pathogenic	Breast and/or ovarian cancer	2023-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000576013	SCV004362913	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast, ovarian, and peritoneal cancer in the literature (PMID: 28961279, 29566657, 31742824). 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.
Baylor Genetics	RCV003335408	SCV005059959	likely pathogenic	Familial cancer of breast	2023-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586741	SCV005076795	pathogenic	Hereditary breast ovarian cancer syndrome	2024-04-10	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2244C>G (p.Tyr748X) 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. The variant was absent in 251216 control chromosomes. c.2244C>G has been reported in the literature in settings of multi-gene panel testing in at least one individual affected with primary peritoneal serous carcinoma (e.g. Sung_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28961279). ClinVar contains an entry for this variant (Variation ID: 430591). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000657691	SCV005089856	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003335408	SCV005417735	pathogenic	Familial cancer of breast		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1+PS4_Supporting
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554339	SCV001775547	pathogenic	Breast carcinoma	2021-08-10	no assertion criteria provided	clinical testing