Submissions for variant NM_007294.4(BRCA1):c.5189A>G (p.Asn1730Ser)

gnomAD frequency: 0.00003  dbSNP: rs80357171

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132266	SCV000187349	likely benign	Hereditary cancer-predisposing syndrome	2020-09-14	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000235134	SCV000210205	uncertain significance	not specified	2016-08-21	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5189A>G at the cDNA level, p.Asn1730Ser (N1730S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 5308A>G. Lee et al. (2010) concluded that BRCA1 Asn1730Ser behaved similar to wild type on in vitro assays interrogating transcription, stability, and binding. BRCA1 Asn1730Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Asn1730Ser occurs at a position that is not conserved and is located within the BRCT 1 domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Asn1730Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000077607	SCV000488026	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-28	criteria provided, single submitter	clinical testing
Department of Pathology and Molecular Medicine, Queen's University	RCV000235134	SCV000588062	benign	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985247	SCV000605907	likely benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132266	SCV000905816	benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235134	SCV000916820	likely benign	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5189A>G (p.Asn1730Ser) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant has been classified as likely benign based on the amount of available evidence and/or prior likelihood of pathogenicity based on variant location and predicted effect (Cline_2019), and this variant was also predicted as neutral by different prediction tools (CAGI class: 2, Padilla_2019). The variant allele was found at a frequency of 2e-05 in 251130 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5189A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Pavlicek_2004, Chen_2006). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant was shown to have no protein folding defect, normal peptide binding activity and specificity, and normal transcriptional activity (Lee_2010, Findlay__2018, Fernandes_2019). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001305771	SCV001495118	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077607	SCV000109410	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-11-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077607	SCV000145375	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077607	SCV001237836	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
PreventionGenetics, part of Exact Sciences	RCV004758633	SCV005347629	uncertain significance	BRCA1-related disorder	2024-04-12	no assertion criteria provided	clinical testing	The BRCA1 c.5189A>G variant is predicted to result in the amino acid substitution p.Asn1730Ser. To our knowledge, this variant has not been reported in the literature in association with disease. An in vitro functional study suggested that the p.Asn1730Ser change resulted in a protein that behaved similar to wild type (Supplementary figure 1B, Lee et al. 2010. PubMed ID: 20516115). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/55447/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.