Submissions for variant NM_032043.3(BRIP1):c.299T>C (p.Met100Thr)

dbSNP: rs587782427

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131481	SCV000186468	likely benign	Hereditary cancer-predisposing syndrome	2024-03-21	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460063	SCV000547369	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the BRIP1 protein (p.Met100Thr). This variant is present in population databases (rs587782427, gnomAD 0.006%). 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: 142390). 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	RCV000663002	SCV000786006	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2018-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131481	SCV000903505	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 100 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 1/251458 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.
Myriad Genetics, Inc.	RCV003315907	SCV004019434	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.