rs533184563
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_032043.3(BRIP1):c.590C>T(p.Ser197Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S197C) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
BRIP1
NM_032043.3 missense
NM_032043.3 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 2.77
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRIP1 | NM_032043.3 | c.590C>T | p.Ser197Phe | missense_variant | 6/20 | ENST00000259008.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRIP1 | ENST00000259008.7 | c.590C>T | p.Ser197Phe | missense_variant | 6/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251352Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135852
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GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461460Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727062
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or prostate cancer and also in unaffected controls (Easton et al., 2016; Isaacsson Velho et al., 2018; Matejcic et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26921362, 29368341, 32832836, 33471991) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 11, 2023 | In the published literature, this variant has been reported in an individual with prostate cancer (PMID: 29368341 (2018)), and in several breast cancer cases and healthy controls in a cancer risk association study (PMID: 33471991 (2021)). This variant has also been observed in the homozygous state in an individual with breast cancer (PMID: 26921362 (2016)). The frequency of this variant in the general population, 0.000054 (7/129100 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2019 | The p.Ser197Phe variant in BRIP1 has been reported in 2 European individuals wit h breast cancer, once in the homozygous state and once in the heterozygous state , as well as one heterozygous individual with prostate cancer (Easton 2016, Velh o 2018). This variant has also been identified in 0.008% (2/24964) of African ch romosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, although the BRIP1 gene has been reported i n association with multiple cancer types, a ClinGen Expert Panel has only defini tively associated the gene to ovarian cancer and refuted its association with br east cancer. There also appears to be limited evidence for an association with p rostate cancer and no good evidence for an association with colon cancer. In sum mary, the clinical significance of the p.Ser197Phe variant is uncertain. ACMG/AM P Criteria applied: PM2_Supporting. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 06, 2023 | Variant summary: BRIP1 c.590C>T (p.Ser197Phe) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 268220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.590C>T has been reported in the literature in individuals affected with breast cancer and prostate cancer (Easton_2016, IsaacssonVelho_2018). Large-scale meta-analyses found that BRIP1 confer high risk for familial ovarian cancer, but not for familial breast cancer (PMID: 29368626, 30733081), therefore, the reported breast cancer patients might not support a pathogenic role for the variant of interest. In addition, one of the reported breast cancer cases was described as homozygous for the variant, however no Fanconi features were noted (Easton_2016). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 3/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 26921362, 29368341). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 2023 | The p.S197F variant (also known as c.590C>T), located in coding exon 5 of the BRIP1 gene, results from a C to T substitution at nucleotide position 590. The serine at codon 197 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was observed within individuals with a personal history of breast cancer (Easton DF et al. J Med Genet, 2016 May;53:298-309). This variant was also identified in multiple cohorts of males diagnosed with prostate cancer (Isaacsson Velho P et al. Prostate, 2018 04;78:401-40; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).This amino acid position is 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 26, 2022 | This missense variant replaces serine with phenylalanine at codon 197 of the BRIP1 protein. Computational prediction 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 individuals affected with breast cancer (PMID: 26921362) and prostate cancer (PMID: 29368341). In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 3/53458 controls; OR=0.884 (95%CI 0.178 to 4.381); p-value=1 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000673). This variant has also been identified in 9/282754 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. - |
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 | Apr 05, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 197 of the BRIP1 protein (p.Ser197Phe). This variant is present in population databases (rs533184563, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362, 29368341). ClinVar contains an entry for this variant (Variation ID: 142178). 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) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 80%. 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. - |
Familial cancer of breast Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 09, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
T;T
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at