Submissions for variant NM_032043.3(BRIP1):c.2994G>C (p.Lys998Asn)

dbSNP: rs757225144

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220971	SCV000273265	likely benign	Hereditary cancer-predisposing syndrome	2023-05-15	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	RCV000217097	SCV000278905	uncertain significance	not provided	2016-02-29	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.2994G>C at the cDNA level, p.Lys998Asn (K998N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Lys998Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BRIP1 Lys998Asn occurs at a position that is not conserved and is located within the region responsible for interacting with BRCA1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRIP1 Lys998Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544259	SCV000633646	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 998 of the BRIP1 protein (p.Lys998Asn). This variant is present in population databases (rs757225144, 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: 229897). 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 asparagine 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.
Mendelics	RCV000989984	SCV001140746	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220971	SCV001339563	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-06	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 998 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 1/250982 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.
Sema4, Sema4	RCV000220971	SCV002533668	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	curation