Submissions for variant NM_032043.3(BRIP1):c.1666T>C (p.Tyr556His)

dbSNP: rs752797989

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012625	SCV001173101	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-14	criteria provided, single submitter	clinical testing	The p.Y556H variant (also known as c.1666T>C), located in coding exon 11 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1666. The tyrosine at codon 556 is replaced by histidine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051923	SCV001216106	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 556 of the BRIP1 protein (p.Tyr556His). This variant is present in population databases (rs752797989, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 819773). 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%. 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	RCV001012625	SCV001349623	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-10	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 556 of the BRIP1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251342 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.