Submissions for variant NM_032043.2(BRIP1):c.2765T>G (p.Leu922Ter) (rs587782410)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131449	SCV000186433	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-31	criteria provided, single submitter	clinical testing	Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx	RCV000216847	SCV000279375	pathogenic	not provided	2018-02-26	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRIP1 c.2765T>G at the cDNA level and p.Leu922Ter (L922X) at the protein level. The substitution creates a nonsense variant, which changes a Leucine to a premature stop codon (TTA>TGA) and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRIP1 Leu922Ter has been reported in at least three individuals with breast cancer (Couch 2015, Easton 2016, Weber-Lassalle 2018). This variant is considered pathogenic.
Counsyl	RCV000410978	SCV000489911	pathogenic	Fanconi anemia, complementation group J	2016-08-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000412207	SCV000489912	pathogenic	Neoplasm of ovary	2016-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV000468535	SCV000547327	pathogenic	Familial cancer of breast; Fanconi anemia, complementation group J	2020-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu922*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587782410, ExAC 0.001%). This variant has been observed in several individuals affected with breast cancer (PMID: 25452441, 26921362). ClinVar contains an entry for this variant (Variation ID: 142366). Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000588116	SCV000699703	likely pathogenic	Hereditary breast and ovarian cancer syndrome	2016-11-25	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.2765T>G (p.Leu922X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121394, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant has been reported in one triple negative breast cancer case as well as a high-risk unaffected control (Couch_2015, Ramus_2015) via publications. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." However, it does need to be noted, a recent publication by Easton_2016 (PMID: 26921362) indicates that the prevalence of truncating variants in BRIP1 have comparable occurrences in controls and cases, for example, p.Arg798Ter was observed in 23 cases and 18 controls, suggesting that truncating variants may not be associated with a substantial increase in breast cancer risk, although the authors do state "BRIP1 screening might have utility for ovarian cancer risk prediction, in combination with other risk factors." Therefore, the variant of interest has been classified as "Likely Pathogenic."
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C.	RCV000131449	SCV000803167	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216847	SCV000887991	pathogenic	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Color	RCV000131449	SCV000903752	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing