rs542698396
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_032043.3(BRIP1):c.3651G>T(p.Trp1217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1217L) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.3651G>T | p.Trp1217Cys | missense_variant | 20/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.3651G>T | p.Trp1217Cys | missense_variant | 20/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250810Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135566
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461048Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726784
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74444
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 06, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with breast cancer (Tung 2016); This variant is associated with the following publications: (PMID: 26976419, 29625052) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 26, 2023 | The p.W1217C variant (also known as c.3651G>T), located in coding exon 19 of the BRIP1 gene, results from a G to T substitution at nucleotide position 3651. The tryptophan at codon 1217 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a cohort of 488 patients with breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This alteration was detected in two different cohorts of Brazilian breast cancer patients (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also detected in a patient with colorectal cancer who was also found to carry a pathogenic mutation in the MSH2 gene (Ricker CN et al. Cancer, 2017 Oct;123:3732-3743). This amino acid position is poorly 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 23, 2023 | This missense variant replaces tryptophan with cysteine at codon 1217 of the BRIP1 protein. Computational prediction tool 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 been reported in one individual affected with breast cancer (PMID: 26976419). This variant has been identified in 2/250810 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. - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Familial cancer of breast Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, Barretos Cancer Hospital | Mar 28, 2022 | ACMG criteria: PM2, PS4_MODERADO, BP4, BP2. *Co-occurrence of pathogenic variant (c.2808_2811del) in BRCA2 gene. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at