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

dbSNP: rs786202760

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226066	SCV000290997	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-09-03	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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. ClinVar contains an entry for this variant (Variation ID: 241635). This missense change has been observed in individual(s) with Fanconi anemia type J or breast cancer (PMID: 16116423, 32986223, 35264596). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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).
GeneDx	RCV000481541	SCV000567795	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1941G>C at the cDNA level, p.Trp647Cys (W647C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGC). This variant has been reported with another missense variant in an individual with Fanconi Anemia, however, phase is not reported (Levitus 2005). BRIP1 Trp647Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tryptophan and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Trp647Cys occurs at a position that is conserved across species and is located in the helicase domain (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Trp647Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000582028	SCV000689297	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	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). This variant has been reported in an individual affected with Fanconi anemia complementation group J (PMID: 16116423). This variant has also been reported in an individual affected with breast cancer (PMID: 25981591). This variant has been identified in 1/251268 chromosomes 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.
Mendelics	RCV000709542	SCV000839372	likely pathogenic	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000990006	SCV001140769	likely pathogenic	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582028	SCV001174419	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.W647C variant (also known as c.1941G>C), located in coding exon 13 of the BRIP1 gene, results from a G to C substitution at nucleotide position 1941. The tryptophan at codon 647 is replaced by cysteine, an amino acid with highly dissimilar properties. In a study of 8 patients diagnosed with Fanconi Anemia complementation group J (FA-J), this variant was seen in a patient who was also found to have another BRIP1 variant, c.2119C>T p.R707C (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5). The phase (in cis or trans) of the two BRIP1 variants was not reported. 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 variant has also been identified in multiple individuals diagnosed with breast cancer (Lajus TB et al. Gene. 2015 Sep;568:215-9; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4	RCV000582028	SCV002531383	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	curation
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003482141	SCV004227975	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-20	criteria provided, single submitter	curation	PM2_sup; PM3_sup, PP3, PS3_sup. According to the ACMG standard criteria we chose these criteria: PS3 (supporting pathogenic): Bharti (2018): "The FANCJ-W647C mutant was determined to be completely inactive for its helicase activity (Supplementary Figure S15) and displayed a dramatic 17-fold reduction in its kcat for ATP hydrolysis (Supplementary Table S4)", PM2 (supporting pathogenic): 1xhet in Gnomad , PM3 (supporting pathogenic): In a study of 8 patients diagnosed with Fanconi Anemia complementation group J (FA-J), this variant was seen in a patient who was also found to have another BRIP1 variant, c.2119C>T p.R707C (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5). , PP3 (supporting pathogenic): BayesDel noAF score 0.2629 REVEL 0.749
Leiden Open Variation Database	RCV000709542	SCV001364545	pathogenic	Fanconi anemia complementation group J	2011-02-07	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.