Submissions for variant NM_032043.3(BRIP1):c.1246C>T (p.Arg416Trp)

gnomAD frequency: 0.00002  dbSNP: rs587780225

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116119	SCV000150028	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 25186627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558154	SCV000633544	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 416 of the BRIP1 protein (p.Arg416Trp). This variant is present in population databases (rs587780225, gnomAD 0.01%). This missense change has been observed in individual(s) with BRIP1-related conditions (PMID: 25186627, 35534704). ClinVar contains an entry for this variant (Variation ID: 128152). 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 not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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	RCV000571154	SCV000673151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The c.1246C>T (p.R416W) alteration is located in exon 9 (coding exon 8) of the BRIP1 gene. This alteration results from a C to T substitution at nucleotide position 1246, causing the arginine (R) at amino acid position 416 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571154	SCV000909785	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 416 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has also been identified in 5/251124 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780058	SCV000917079	uncertain significance	not specified	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.1246C>T (p.Arg416Trp) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain, DinG/Rad3-type and Helicase-like, DEXD box c2 type domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245884 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer (2e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1246C>T has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer. This report do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137632	SCV003806828	uncertain significance	Familial cancer of breast	2022-07-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderated, BP4 supporting