Submissions for variant NM_032043.3(BRIP1):c.3050C>T (p.Pro1017Leu)

gnomAD frequency: 0.00001  dbSNP: rs747907706

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165849	SCV000216598	likely benign	Hereditary cancer-predisposing syndrome	2018-12-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000231204	SCV000291030	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-06-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1017 of the BRIP1 protein (p.Pro1017Leu). This variant is present in population databases (rs747907706, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian and/or breast cancer (PMID: 26315354, 26921362). ClinVar contains an entry for this variant (Variation ID: 186283). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000586787	SCV000567106	uncertain significance	not provided	2018-05-14	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.3050C>T at the cDNA level, p.Pro1017Leu (P1017L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant was identified in 3/13,213 cases and 2/5,242 controls in a breast cancer case-control study, as well as in at least one individual with ovarian cancer (Ramus 2015, Easton 2016). BRIP1 Pro1017Leu was not observed at a significant frequency in large population cohorts (Lek 2016). BRIP1 Pro1017Leu is located in the BRCA1 binding domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRIP1 Pro1017Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549276	SCV000699711	uncertain significance	not specified	2021-07-12	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3050C>T (p.Pro1017Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3050C>T has been reported in the literature in the settings of multigene panel testing in an individual with epithelial ovarian cancer (example, Ramus_2016) and in unaffected controls as well as individuals affected with breast cancer from a UK cohort (example, Easton_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000662372	SCV000784765	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2017-01-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165849	SCV000911428	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262876	SCV001440910	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001549276	SCV002065637	uncertain significance	not specified	2018-09-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262876	SCV004019378	uncertain significance	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001262876	SCV004031079	uncertain significance	Familial cancer of breast	2023-07-25	criteria provided, single submitter	clinical testing	The BRIP1 c.3353A>G (p.Asn1118Ser) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in 3 of 13,213 breast cancer cases and 2 of 5,242 controls in case control study (PMID: 26921362), and in 1 of in 3,236 invasive ovarian carcinoma patients and 0 of 3,431 control patients of European origin (PMID: 26315354). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/), and in 1 of 1,358 control individuals collected as part of a non-cancer studies (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.