ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.107C>A (p.Ser36Tyr)

dbSNP: rs183557525
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204917 SCV000259787 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 36 of the BRCA1 protein (p.Ser36Tyr). This variant is present in population databases (rs183557525, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 21735045, 24695549, 30675319). ClinVar contains an entry for this variant (Variation ID: 219742). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 24695549, 25823446, 26689913, 30696104). 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.
GeneDx RCV000587859 SCV000566735 uncertain significance not provided 2019-08-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21735045, 30675319, 24695549, 26689913, 25823446, 27882536, 30696104)
Ambry Genetics RCV000563749 SCV000661037 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-31 criteria provided, single submitter clinical testing The p.S36Y variant (also known as c.107C>A), located in coding exon 2 of the BRCA1 gene, results from a C to A substitution at nucleotide position 107. The serine at codon 36 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of Lebanese individuals referred for BRCA1/2 testing (Farra C et al. Hered Cancer Clin Pract, 2019 Jan;17:4), as well as Cypriot populations in both familial and sporadic breast cancer patients (Christou CM et al. PLoS ONE. 2014 Apr;9(4):e93400; Hadjisavvas A et al. BMC Cancer. 2010 Aug;10:447). A detailed functional analysis including protein expression, co-immunoprecipitation, and co-localization analysis indicates that this variant is defective, however, studies disagree about the BARD1 binding defect (Christou CM et al. PLoS ONE. 2014 Apr;9(4):e93400; Starita LM et al. Genetics. 2015 Jun;200(2):413-22). Additionally, this alteration was found to be neutral in drug sensitivity, homologous recombination repair, and mammalian two-hybrid assays (Bouwman P et al. Clin Cancer Res, 2020 09;26:4559-4568; Clark, KA et al. Am J Hum Genet 2022 06;109(6):1153-1174). 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 conflicting at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000563749 SCV000682934 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-18 criteria provided, single submitter clinical testing This missense variant replaces serine with tyrosine at codon 36 of the BRCA1 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). Functional studies have reported conflicting impact of this variant protein on ubiquitin conjugation, as two studies have found subcellular mislocalization from the nucleus to the cytoplasm and impaired interaction with a ubiquitin ligation protein (PMID: 24695549, 30696104) while a ubiquitin ligase assay found the variant protein to have near wild-type activity (PMID: 25823446). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 24695549, 27882536). This variant has also been identified in 1/250860 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003389638 SCV000698830 uncertain significance not specified 2023-10-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.107C>A (p.Ser36Tyr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) 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 2e-05 in 253208 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.107C>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Christou_2014, Farra_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Functional studies reported contradicting outcomes of the variant on the function of BRCA1 (Christou_2014, Lu_2015, Starita_2015, Bouwman_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32546644, 30696104, 24695549, 35659930, 30675319, 26689913, 21735045, 25823446). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000989916 SCV001140648 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000989916 SCV004031210 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2023-06-26 criteria provided, single submitter clinical testing The BRCA1 c.107C>A (p.Ser36Tyr) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 27882536, 30675319). It was found to be associated with increased breast cancer risk in a small case-control study of 1174 cases and 1109 controls in the Cypriot population (OR = 3.47) (PMID: 20727220, 24695549). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). The in silico tool REVEL predicts a deleterious effect on protein function, however functional assays are not in agreement about the impact of this variant. In a functional study where the mutant was transfected into a cell line, the p.Ser36Tyr variant exhibited low protein expression, cellular mislocalization to the cytoplasm, and impaired interaction with BARD1 (PMID: 24695549). A massively parallel functional analysis measuring E3 ubiquitin ligase activity and BARD1 binding indicated that this variant behaves similar to the wild-type (PMID: 25823446). Finally, cisplatin and olaparib sensitivity assays and homologous recombination DNA repair assays indicated that this variant behaved similar to the wild-type (PMID: 32546644). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Revvity Omics, Revvity Omics RCV000587859 SCV004234649 uncertain significance not provided 2023-02-17 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.