Submissions for variant NM_007294.4(BRCA1):c.115T>A (p.Cys39Ser)

dbSNP: rs80357164

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509615	SCV000608086	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-06	criteria provided, single submitter	clinical testing	The p.C39S pathogenic mutation (also known as c.115T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 115. The cysteine at codon 39 is replaced by serine, an amino acid with dissimilar properties. The p.C39S alteration is located in a critical region of the BRCA1 protein RING domain. A functional study has shown that changes at this residue alter the structure of the RING domain and negatively impact ubiquitin-ligase activity and BARD1 binding activity (Starita LM et al. Genetics. 2015 Jun;200(2):413-22). This alteration was also shown to be non-functional in a high throughput genome editing haploid cell survival assay (Findlay G et al. Nature 2018 10;562(7726):217-222). The p.C39S variant has been reported in breast and/or ovarian cancer families from Spain. (Blay P et al. BMC Cancer 2013;13:243; Rebbeck T et al. Hum. Mutat. 2018 05;39(5):593-620). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Brzovic PS et al. Proc. Natl. Acad. Sci. U.S.A. 2003 May;100(10):5646-51). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759489	SCV000888834	pathogenic	not provided	2019-12-12	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in families with hereditary breast and ovarian cancer, and it is situated within an important functional domain at an amino acid residue with at least two other reported pathogenic variations (PMIDs: 15235020 (2004), 17262179 (2007) and 25823446 (2015)). Assessment of experimental evidence regarding the effect of this variant suggests it is detrimental to normal function (PMIDs: 25823446 (2015) and 16403807 (2006)). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781001	SCV000918746	pathogenic	Hereditary breast ovarian cancer syndrome	2019-09-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.115T>A (p.Cys39Ser) results in a non-conservative amino acid change located in the Zinc finger, C3HC4 RING-type domain (IPR018957) 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 251086 control chromosomes (gnomAD). c.115T>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Beristain_2007, Sweet_2010, Blay_2013, Mgbemena_2017, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Starita_2015). Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000509615	SCV001351373	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-07-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 39 in the RING domain of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Multiple functional studies have shown that this variant causes a reduction in BARD1 binding and/or ubiquitin-ligase activity (PMID: 12732733, 16403807, 25823446). This variant has been shown to cause loss-of-function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 17262179; Color internal data) and in an individual affected with ovarian cancer (PMID: 28122244). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV000781001	SCV001579181	pathogenic	Hereditary breast ovarian cancer syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 39 of the BRCA1 protein (p.Cys39Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys39 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9808526, 11320250, 12827452, 17319787, 18500671, 19543972, 21725363, 21922593, 21990134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 12732733, 16403807, 22843421, 25823446). 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. ClinVar contains an entry for this variant (Variation ID: 54151). This variant is also known as 234T>A. This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 17262179, 23683081).
Baylor Genetics	RCV000111803	SCV004215116	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-28	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111803	SCV000144348	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	1998-03-04	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111803	SCV001241899	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro