Submissions for variant NM_032043.3(BRIP1):c.1941G>T (p.Trp647Cys)

dbSNP: rs786202760

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165735	SCV000216476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.W647C variant (also known as c.1941G>T), located in coding exon 13 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1941. The tryptophan at codon 647 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was not observed in 706 cases with ovarian cancer or 6341 cases with breast cancer and was observed in 1/36687 healthy controls (Weber-Lassalle N et al. Breast Cancer Res., 2018 01;20:7). Another alteration that results in the same amino acid change (c.1941G>C) has been identified in conjunction with a BRIP1 mutation in an individual diagnosed with Fanconi Anemia complementation group J (FA-J); Western blot demonstrated attenuated protein expression in this individual (Levitus M, Nat. Genet. 2005 Sep; 37(9):934-5). Functional assays indicate this alteration inactivates the helicase activity of the protein, and severely compromises its ability to hydrolyze ATP (Bharti SK et al. Nucleic Acids Res., 2018 Jul;46:6238-6256). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000410856	SCV000489991	uncertain significance	Fanconi anemia complementation group J	2016-09-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000412383	SCV000489992	uncertain significance	Neoplasm of ovary	2016-09-07	criteria provided, single submitter	clinical testing
Invitae	RCV000542964	SCV000633583	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 647 of the BRIP1 protein (p.Trp647Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25981591). ClinVar contains an entry for this variant (Variation ID: 186189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165735	SCV000684170	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 647 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant protein displays reduced helicase activity in an in vitro assay (PMID: 29788478). While this variant has not been reported in individuals affected with BRIP1-associated diseases in the literature, a different variant (c.1941G>C) resulting in the same amino acid change has been reported in individuals affected with Fanconi anemia and breast cancer (PMID: 16116423, 25981591). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778762	SCV002014965	uncertain significance	not specified	2021-10-18	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1941G>T (p.Trp647Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251268 control chromosomes. c.1941G>T has been reported in the literature as a VUS in settings of multigene panel testing in at-least two individuals affected with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 (Fonfria_2021). One of these individuals reported a triple negative subtype (ER/PR/HER2), while the other reported a triple positive subtype of breast cancer. Furthermore, a different nucleotide substitution, c.1941G>C, that results in an identical amino acid substitution, namely p.Trp647Cys, has been identified along with another FANCJ (BRIP1) allele in an individual affected with Fanconi Anemia (Levitus_2005). Another study reported this specific nucleotide variant in controls but not in breast cancer cases (Weber-Lassalle_2018). Some reports do not specify the exact nucleotide alteration and limit reporting to the affected protein (example, Guo_2016, Bharti_2018 described below). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bharti_2018). The most pronounced variant effect results in <10% of normal helicase activity as evidenced by a decrease in Kcat for ATP hydrolysis in a recombinant FANCJ protein expressing baculovirus system. Four 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 uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV001847787	SCV002104363	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Fonfria 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Another substitution, BRIP1 1941G>C, resulting in the same Trp647Cys missense variant has been observed in at least one individual with breast cancer and has been co-observed with a second BRIP1 variant, phase unknown, in an individual with Fanconi anemia (Levitus 2005, Lajus 2015). Furthermore BRIP1 1941G>C (Trp647Cys) has been associated with absent helicase activity and reduced ATP hydrolysis (Bharti 2018).; This variant is associated with the following publications: (PMID: 16116423, 29368626, 23276657, 17145708, 29788478, 25981591, 34204722)
Fulgent Genetics, Fulgent Genetics	RCV000542964	SCV002786530	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-02-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316047	SCV004019385	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.
Baylor Genetics	RCV003316047	SCV004214774	uncertain significance	Familial cancer of breast	2023-09-02	criteria provided, single submitter	clinical testing