rs80357002
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.4765C>T(p.Arg1589Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,884 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. R1589P) has been classified as Likely benign.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.4765C>T | p.Arg1589Cys | missense_variant | 15/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.4765C>T | p.Arg1589Cys | missense_variant | 15/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 28, 2020 | DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4765C>T, in exon 15 that results in an amino acid change, p.Arg1589Cys. This sequence change has been described in the gnomAD database in three individuals (dbSNP rs80357002). The p.Arg1589Cys change has been described in one individual from a hereditary breast and ovarian cancer family (PMID: 16267036). The p.Arg1589Cys change affects a poorly conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Cys change remains unknown at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2024 | Variant summary: BRCA1 c.4765C>T (p.Arg1589Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has been reported in HBOC families, however with limited information (i.e. no data about co-occurrence and cosegregation provided) (example, Judkins_2005, Lincoln_2015, Kim_2020). However, a reputable database (BIC) cites the variant to co-occur with a pathogenic BRCA2 variant (c.1929delG), suggesting that it was not a primary cause of disease in the patient. A large case-control study evaluating breast cancer genetic risk also reported this variant was absent in the case cohorts (Dorling_2021, 1/53461 controls). In addition, this variant had similar transcription activation activity in comparison to wildtype (Woods_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 16267036, 31907386, 26207792, 15385441, 28781887). ClinVar contains an entry for this variant (Variation ID: 55283). Based on the evidence outlined above, the variant was classified as uncertain significance-possibly benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2016 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Endocrinology Laboratory, Christian Medical College | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 23, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 10, 2012 | - - |
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 21, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 28, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | May 30, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2018 | 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at