17-43106487-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.181T>C(p.Cys61Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 28
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Uncertain:1Other:1
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Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 61 of the BRCA1 protein (p.Cys61Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 19329713, 25948282, 26757417, 30078507). This variant is also known as 300T>C. ClinVar contains an entry for this variant (Variation ID: 54360). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 22843421, 25823446, 30209399). This variant disrupts the p.Cys61 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7894493, 9525870, 11278247, 19594371, 19770520, 22172724). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Variant summary: BRCA1 c.181T>C (p.Cys61Arg) results in a non-conservative amino acid change located in the RING domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.181T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report somewhat conflicting experimental evidence evaluating an impact on homology directed repair (HDR) capacity (example, Starita_2015, Findlay_2018). The most pronounced variant effect in one study reports a loss of E3 ligase activity, BARD1 binding activity and a predicted loss of homology directed repair (HDR) capacity (Starita_2015). However, a subsequent study by the same authors reports an intermediate HDR activity (Findlay_2018). One clinical diagnostic laboratory and one consortium (CIMBA, captured in Rebbeck_2018) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Pathogenic:1
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C61R variant (also known as c.181T>C), located in coding exon 3 of the BRCA1 gene, results from a T to C substitution at nucleotide position 181. The cysteine at codon 61 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with BRCA1-related hereditary breast and ovarian cancer syndrome (Al-Mulla F et al. J Clin Pathol, 2009 Apr;62:350-6; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Ng PS et al. Clin Genet, 2016 Oct;90:315-23; Li A et al. Gynecol Oncol, 2018 Oct;151:145-152). One functional study found that this nucleotide substitution to have intermediate function in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Another variant at the same codon, p.C61G (c.181T>G), represents a common mutation in European populations, and has been identified in patients with breast, ovarian, pancreatic, and prostate cancer (Gronwald J et al. J. Med. Genet. 2006 May;43:424-8; Janaviius R. EPMA J. 2010 Sep;1:397-412; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Brand R et al. Cancer. 2018 Sep;124:3520-3527; Ibrahim M et al. BMC Cancer. 2018 02;18:179), and has been shown to be deleterious in functional studies (Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature. 2018 10;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
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