Submissions for variant NM_032043.3(BRIP1):c.2854A>G (p.Ile952Val)

gnomAD frequency: 0.00003  dbSNP: rs200239986

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215700	SCV000277228	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The p.I952V variant (also known as c.2854A>G), located in coding exon 18 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2854. The isoleucine at codon 952 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in 2/235 high-risk Korean breast cancer patients who previously tested negative for mutations in the BRCA1/2 genes (Kim H et al. Cancer Res Treat. 2016 Jul;48:955-61). This alteration has also been reported in a head and neck squamous cell carcinoma cancer patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). 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.
GeneDx	RCV000214349	SCV000278903	uncertain significance	not provided	2023-10-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25589003, 26790966, 26689913, 26709662, 29338689, 31214711, 35681111, 11301010, 32566746, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227974	SCV000291026	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 952 of the BRIP1 protein (p.Ile952Val). This variant is present in population databases (rs200239986, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer, head and neck cancer, biliary tract cancer, and prostate cancer (PMID: 26689913, 26790966, 31214711, 36243179). ClinVar contains an entry for this variant (Variation ID: 232950). 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.
Counsyl	RCV000662447	SCV000784918	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215700	SCV000910923	likely benign	Hereditary cancer-predisposing syndrome	2015-12-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000989990	SCV001140752	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030466	SCV001193526	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-03-30	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000709536	SCV001284865	uncertain significance	Fanconi anemia complementation group J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000214349	SCV002046719	uncertain significance	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000989990	SCV004019299	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.
Department of Human Genetics, Hannover Medical School	RCV000989990	SCV005326370	uncertain significance	Familial cancer of breast	2024-09-19	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001194733	SCV001364504	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.