rs569696977
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_032043.3(BRIP1):c.1139G>T(p.Ser380Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S380G) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.1139G>T | p.Ser380Ile | missense_variant, splice_region_variant | 8/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1139G>T | p.Ser380Ile | missense_variant, splice_region_variant | 8/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251206Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135746
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456782Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725026
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74474
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 31, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 13, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 08, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2023 | 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. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 17, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at