chr17-61716003-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1
The NM_032043.3(BRIP1):c.2440C>T(p.Arg814Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,608,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R814H) has been classified as Uncertain significance.
Frequency
Consequence
NM_032043.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRIP1 | NM_032043.3 | c.2440C>T | p.Arg814Cys | missense_variant | 17/20 | ENST00000259008.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRIP1 | ENST00000259008.7 | c.2440C>T | p.Arg814Cys | missense_variant | 17/20 | 1 | NM_032043.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000257 AC: 39AN: 152006Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000472 AC: 118AN: 250258Hom.: 0 AF XY: 0.000443 AC XY: 60AN XY: 135316
GnomAD4 exome AF: 0.000157 AC: 228AN: 1456774Hom.: 0 Cov.: 30 AF XY: 0.000179 AC XY: 130AN XY: 724466
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152120Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27AN XY: 74372
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:2Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 08, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 26, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 18, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 27, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2016 | Variant summary: The BRIP1 c.2440C>T (p.Arg814Cys) variant located in the P-loop containing nucleoside triphosphate hydrolase and ATP-dependent helicase, C-terminal domains (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 58/120652 (1/2080), predominantly in the East Asian cohort, 47/8492 (1/180), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. Therefore, suggesting the variant is a common polymorphism found in population(s) of East Asian origin. The variant of interest has been reported in multiple affected individuals via publications as a germline and somatic mutation. In addition multiple clinical diagnostic laboratories cite the variant with conflicting classifications of "uncertain significance" or "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Likely Benign." - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Aug 13, 2019 | Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. - |
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.Arg814Cys variant was identified in 3 of 1382 proband chromosomes (frequency: 0.002) from individuals or families with breast, colorectal cancer (Lin 2016, Ng 2016, Pearlman 2016). The variant was also identified in dbSNP (ID: rs201869624) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx; classified as likely benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar, Invitae). The variant was not identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in control databases in 117 of 276074 chromosomes at a frequency of 0.000424 in east Asian and south Asian populations, 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.Arg814 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2016 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 23, 2023 | - - |
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Fanconi anemia complementation group J Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Familial cancer of breast Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 02, 2023 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at