Submissions for variant NM_032043.3(BRIP1):c.1759C>G (p.His587Asp)

gnomAD frequency: 0.00002  dbSNP: rs876660519

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218989	SCV000278016	likely benign	Hereditary cancer-predisposing syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473133	SCV000547265	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 587 of the BRIP1 protein (p.His587Asp). 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: 233608). Invitae Evidence 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 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.
GeneDx	RCV000482369	SCV000570517	uncertain significance	not provided	2020-11-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in any breast cancer cases, but was observed in unaffected controls in published literature (Easton 2016); This variant is associated with the following publications: (PMID: 26921362)
Color Diagnostics, LLC DBA Color Health	RCV000218989	SCV000689282	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 587 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 been identified in 1/31400 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.
Counsyl	RCV000662848	SCV000785715	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-11-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482369	SCV001469474	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000218989	SCV002531375	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316229	SCV004019313	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	RCV003316229	SCV005059228	uncertain significance	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing