Submissions for variant NM_032043.3(BRIP1):c.2867C>T (p.Ser956Leu)

gnomAD frequency: 0.00001  dbSNP: rs761639530

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206417	SCV001377725	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 956 of the BRIP1 protein (p.Ser956Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 31871109). ClinVar contains an entry for this variant (Variation ID: 937416). 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.
Genetic Services Laboratory, University of Chicago	RCV001819895	SCV002065243	uncertain significance	not specified	2021-04-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.2867C>T, in exon 19 that results in an amino acid change, p.Ser956Leu. This sequence change has been described in gnomAD with a frequency of 0.012% in the African sub-population (dbSNP rs761639530). The p.Ser956Leu change affects a poorly conserved amino acid residue located in a domain of the BRIP1 protein that is not known to be functional. The p.Ser956Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with BRIP1-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Ser956Leu change remains unknown at this time.
Ambry Genetics	RCV002436795	SCV002747037	likely benign	Hereditary cancer-predisposing syndrome	2024-08-28	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.
Fulgent Genetics, Fulgent Genetics	RCV001206417	SCV002779280	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV003442769	SCV004169469	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a breast cancer study, but it is not clear if the variant was identified in case(s) or control(s) (Adedokun et al., 2020); This variant is associated with the following publications: (PMID: 31871109)