Submissions for variant NM_032043.3(BRIP1):c.1850T>C (p.Leu617Ser)

dbSNP: rs1064794095

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487183	SCV000567805	uncertain significance	not provided	2017-06-29	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1850T>C at the cDNA level, p.Leu617Ser (L617S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Leu617Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Leu617Ser occurs at a position that is conserved across species and is located within the helicase domain III (Cantor 2011). Based on currently available evidence, it is unclear whether BRIP1 Leu617Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554110	SCV000633578	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 617 of the BRIP1 protein (p.Leu617Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 419768). 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) 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.
Ambry Genetics	RCV001013389	SCV001173968	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing	The p.L617S variant (also known as c.1850T>C), located in coding exon 12 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1850. The leucine at codon 617 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was observed in 0/706 cases with ovarian cancer, 0/6341 cases with breast cancer, and 1/36687 controls (Weber-Lassalle N et al. Breast Cancer Res., 2018 01;20:7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV001821394	SCV002068100	uncertain significance	not specified	2020-04-21	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.1850T>C, in exon 13 that results in an amino acid change, p.Leu617Ser. This sequence change has been described in the gnomAD database with a frequency of 0.0009% in European populations (dbSNP rs1064794095). The p.Leu617Ser change affects a highly conserved amino acid residue located in a domain of the BRIP1 protein that is known to be functional. The p.Leu617Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This c.1850T>C sequence change has not been reported in the literature in individuals with BRIP1-related disorders. Due to the lack of sufficient data, the clinical significance of the p.Leu617Ser change remains unknown at this time.
Color Diagnostics, LLC DBA Color Health	RCV001013389	SCV004362925	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 617 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a study of 6341 patients affected with breast cancer, 706 patients affected with ovarian cancer, and 2189 geographically matched female controls, this variant reported in 1 control individual but was absent in patients affected with cancer (PMID:29368626). This variant has been identified in 1/251448 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.