rs147755155
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_032043.3(BRIP1):c.2087C>T(p.Pro696Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. P696S) 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.2087C>T | p.Pro696Leu | missense_variant | 14/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2087C>T | p.Pro696Leu | missense_variant | 14/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251352Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135832
GnomAD4 exome AF: 0.0000752 AC: 110AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727216
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74436
ClinVar
Submissions by phenotype
not provided Uncertain:4
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 | Jan 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 11, 2018 | The BRIP1 c.2087C>T; p.Pro696Leu variant (rs147755155) is reported in the literature in six individuals with breast cancer, and one unaffected control (Easton 2016). This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 128167), and is found in the general population with an overall allele frequency of 0.005% (13/277092 alleles) in the Genome Aggregation Database. The proline at codon 696 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Pro696Leu variant is uncertain at this time. REFERENCES Easton DF et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016 May;53(5):298-309. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in breast and ovarian cancer cases, but also in control groups (PMID: 26921362, 29368626, 31882575, 33471991, 36035419); This variant is associated with the following publications: (PMID: 26921362, 29368626, 27153395, 36035419, 11301010, Milano2023[Pre-Print], 33471991, 31882575) - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2023 | The p.P696L variant (also known as c.2087C>T), located in coding exon 13 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2087. The proline at codon 696 is replaced by leucine, an amino acid with similar properties. In one study, this alteration was detected in 6/13213 cases with breast cancer and 0/5242 controls in a UK cohort, and in 0/1853 cases with breast cancer and 1/2001 controls in an Australian cohort (Easton DF et al. J. Med. Genet. 2016 05;53:298-309). In another study, this alteration was observed in 0/706 cases with ovarian cancer, 1/6341 cases with breast cancer and 5/36687 controls (Weber-Lassalle N et al. Breast Cancer Res. 2018 Jan;20:7). This variant was reported in two Norwegian sisters diagnosed with ovarian cancer; one of them also carried an ATM founder mutation and the other did not (Jarhelle E et al. Sci Rep, 2019 12;9:19986). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 | Nov 22, 2022 | This missense variant replaces proline with leucine at codon 696 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with ovarian cancer (PMID: 31882575), over twenty individuals with breast and/or ovarian cancer (PMID: 26921362, 27153395, 29368626, 33471991, 36035419) and nine unaffected control individuals (PMID: 26921362, 33471991). Large case-control studies have been inconclusive about whether this variant is associated with increased breast cancer risk (PMID: 26921362, 33471991). This variant has been identified in 16/282756 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 | curation | Sema4, Sema4 | Dec 26, 2021 | - - |
Familial cancer of breast Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 19, 2022 | The BRIP1 c.2087C>T (p.Pro696Leu) missense change has a maximum subpopulation frequency of 0.0093% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in siblings with ovarian cancer (PMID: 31882575) where one of the siblings also harbored a pathogenic variant in the ATM gene. It has also been reported in individuals with a personal and/or family history of breast cancer (PMID: 26921362, 27153395, 32885271). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 09, 2022 | Variant summary: BRIP1 c.2087C>T (p.Pro696Leu) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal (IPR006555) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 255354 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome (6.3e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.2087C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. However, a recent case-control study showed that this variant is not associated with breast cancer (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 | May 24, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 696 of the BRIP1 protein (p.Pro696Leu). This variant is present in population databases (rs147755155, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362, 29368626). ClinVar contains an entry for this variant (Variation ID: 128167). 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 expected to disrupt BRIP1 protein function. 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. - |
Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 19, 2017 | - - |
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 22, 2021 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRIP1 p.Pro696Leu variant was not identified in the literature nor was it identified in the Cosmic, database. The variant was identified in dbSNP (ID: rs147755155) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae), Clinvitae (classified as uncertain significance by ClinVar, Invitae), MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 13 of 277092 chromosomes at a frequency of 0.00005 in the following populations: European in 10 of 126608 chromosomes (freq. 0.0001), African in 1 of 24030 chromosomes (freq. 0.00004), Latino in 1 of 34404 chromosomes (freq. 0.00003), Finnish in 1 of 25794 chromosomes (freq. 0.00004), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Pro696 residue is conserved in across mammals and other organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the DNA helicase (DNA repair), Rad3 type functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at