Submissions for variant NM_032043.3(BRIP1):c.1139G>T (p.Ser380Ile)

dbSNP: rs569696977

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580380	SCV000684112	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 380 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRIP1-related disorders in the literature. In an international breast cancer case-control meta-analysis, this variant was absent in 60466 cases and detected in 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251206 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758984	SCV000887975	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822100	SCV000962886	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 380 of the BRIP1 protein (p.Ser380Ile). This variant is present in population databases (rs569696977, gnomAD 0.007%). 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: 489805). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	RCV000580380	SCV001170122	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	The p.S380I variant (also known as c.1139G>T), located in coding exon 7 of the BRIP1 gene, results from a G to T substitution at nucleotide position 1139. The serine at codon 380 is replaced by isoleucine, an amino acid with dissimilar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003459421	SCV004217122	uncertain significance	Familial cancer of breast	2023-05-13	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003459421	SCV005089940	uncertain significance	Familial cancer of breast	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 380 of the BRIP1 protein (p.Ser380Ile).This amino acid position is not well conserved (PhyloP=1.76) . This variant is present in population databases (rs569696977, gnomAD 0.007%). This variant has not been reported inthe literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 489805). In addition, this alteration is predicted to be tolerated by in silico analysis. 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.