Submissions for variant NM_032043.3(BRIP1):c.3275C>T (p.Pro1092Leu)

gnomAD frequency: 0.00001  dbSNP: rs587780830

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123358	SCV000166681	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1092 of the BRIP1 protein (p.Pro1092Leu). This variant is present in population databases (rs587780830, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 136149). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV000130186	SCV000185023	likely benign	Hereditary cancer-predisposing syndrome	2019-02-21	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.
GeneDx	RCV000442394	SCV000512424	likely benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000662393	SCV000784806	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2016-12-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130186	SCV000903041	likely benign	Hereditary cancer-predisposing syndrome	2017-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442394	SCV000917080	uncertain significance	not specified	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.3275C>T (p.Pro1092Leu) results in a non-conservative amino acid change in 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 7.7e-06 in 261342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3275C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 136149). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284121	SCV001469741	uncertain significance	not provided	2019-11-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315827	SCV004019426	uncertain significance	Familial cancer of breast	2023-03-01	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.
Institute of Immunology and Genetics Kaiserslautern	RCV004584610	SCV005073985	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2024-07-02	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2_P, BP4; Variant was found in heterozygous state
PreventionGenetics, part of Exact Sciences	RCV004732691	SCV005360136	uncertain significance	BRIP1-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The BRIP1 c.3275C>T variant is predicted to result in the amino acid substitution p.Pro1092Leu. This variant has been reported in an individual with breast cancer (Table S1, Easton et al. 2016. PubMed ID: 26921362). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/136149/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.