Submissions for variant NM_032043.3(BRIP1):c.931T>C (p.Tyr311His)

dbSNP: rs1603343412

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799195	SCV000938848	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-31	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 311 of the BRIP1 protein (p.Tyr311His). This variant is not present in population databases (gnomAD no frequency). 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: 645160). 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 not expected to disrupt BRIP1 protein function with a negative 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.
Ambry Genetics	RCV001019170	SCV001180493	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-23	criteria provided, single submitter	clinical testing	The p.Y311H variant (also known as c.931T>C), located in coding exon 7 of the BRIP1 gene, results from a T to C substitution at nucleotide position 931. The tyrosine at codon 311 is replaced by histidine, an amino acid with similar properties. This alteration was identified in 1/13213 cases of breast cancer and 0/5242 controls from the United Kingdom (Easton DF et al. J. Med. Genet., 2016 05;53:298-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001019170	SCV004362955	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 311 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1/13213 heterozygous individuals affected with breast cancer and was absent in 5242 controls (PMID: 26921362). 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.