rs786201819
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_032043.3(BRIP1):āc.1040T>Cā(p.Leu347Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L347I) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
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.1040T>C | p.Leu347Pro | missense_variant | 8/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.1040T>C | p.Leu347Pro | missense_variant | 8/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461770Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727200
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 28, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 18, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 10, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2022 | The p.L347P variant (also known as c.1040T>C), located in coding exon 7 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1040. The leucine at codon 347 is replaced by proline, an amino acid with similar properties. This alteration was detected in 1/1824 patients with triple negative breast cancer, who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). However, in two other studies this variant has not been observed in breast or ovarian cases but has been seen in controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Weber-Lassalle N et al. Breast Cancer Res. 2018 Jan;20:7). In one study, this alteration was classified as a loss of function mutation based on its failure to confer resistance to either cisplatin or mitomycin C treatment (Calvo JA et al. Mol Cancer Res, 2021 06;19:1015-1025). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 15, 2022 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the BRIP1 protein (p.Leu347Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 184958). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 33619228). 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. - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 22, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: failed to confer resistance to inter-strand crosslink-inducing agents (Calvo et al., 2021); Observed in individuals with breast cancer, but also in healthy control subjects (Couch et al., 2015; Ramus et al., 2015; Weber-Lassalle et al., 2018); This variant is associated with the following publications: (PMID: 25452441, 26315354, 29368626, 33619228) - |
Ovarian neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 22, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at