Submissions for variant NM_007294.4(BRCA1):c.110C>A (p.Thr37Lys)

dbSNP: rs80356880

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111781	SCV000244295	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-08-10	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1
Fulgent Genetics, Fulgent Genetics	RCV000763401	SCV000894127	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378528	SCV001576113	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 54131). 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 25823446, 27272900, 30209399). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. This missense change has been observed in individual(s) with breast cancer (PMID: 19543972, 25823446, 28664506, 30564348). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 37 of the BRCA1 protein (p.Thr37Lys).
Ambry Genetics	RCV002433536	SCV002744812	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-20	criteria provided, single submitter	clinical testing	The p.T37K pathogenic mutation (also known as c.110C>A), located in coding exon 2 of the BRCA1 gene, results from a C to A substitution at nucleotide position 110. The threonine at codon 37 is replaced by lysine, an amino acid with similar properties. This alteration was identified in a Malaysian woman diagnosed with triple-negative breast cancer at age 31, as well as an African America woman diagnosed with bilateral breast cancer, at ages 27 and 33 (Yang XR et al. Breast Cancer Res Treat. 2017 Oct;165:687-697; Skendelas JP et al. Clin Case Rep. 2018 Dec;6:2457-2462). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). Another alteration at the same codon, p.T37R (c.110C>G), has also been determined to be functionally and structurally deleterious (Findlay GM et al. Nature. 2018 10;562:217-222; Morris JR et al. Hum Mol Genet. 2006; 15:599-606; Ransburgh DJ et al. Cancer Res. 2010; 70:988-95; Towler WI et al. Hum Mutat. 2013; Ruffner H et al. Proc. Natl. Acad. Sci. U.S.A. 2001 Apr; 98(9):5134-9; Zhu Q et al. Nature 2011 Sep; 477(7363):179-84; Brzovic PS et al. Nat. Struct. Biol. 2001 Oct;8(10):833-7; Ambry Internal Data). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000111781	SCV004215155	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-04-19	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111781	SCV000144321	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111781	SCV001242839	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro