Submissions for variant NM_032043.3(BRIP1):c.1303C>T (p.His435Tyr)

dbSNP: rs1060501758

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475043	SCV000547311	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 435 of the BRIP1 protein (p.His435Tyr). 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: 407833). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 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.
Counsyl	RCV000663159	SCV000786316	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2018-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001525373	SCV001735451	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 435 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Ambry Genetics	RCV001525373	SCV002689867	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-11	criteria provided, single submitter	clinical testing	The p.H435Y variant (also known as c.1303C>T), located in coding exon 8 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1303. The histidine at codon 435 is replaced by tyrosine, 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.
Myriad Genetics, Inc.	RCV003316563	SCV004019317	uncertain significance	Familial cancer of breast	2023-02-27	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	RCV003316563	SCV005059250	uncertain significance	Familial cancer of breast	2024-02-16	criteria provided, single submitter	clinical testing