Submissions for variant NM_007294.4(BRCA1):c.1843TCT[1] (p.Ser616del)

dbSNP: rs80358329

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031011	SCV001161491	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	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 1 based on posterior probability = 5.40E-06
Invitae	RCV000047608	SCV000075621	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000031011	SCV000154019	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-02-05	criteria provided, single submitter	literature only
Ambry Genetics	RCV000131329	SCV000186303	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031011	SCV000195894	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000679684	SCV000209931	likely benign	not provided	2021-03-24	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22874498, 19941162, 30263132, 11183185, 15726418, 20104584, 22034289, 24729269, 22425665, 16267036, 29892687, 31131967)
PreventionGenetics, part of Exact Sciences	RCV003891452	SCV000311786	benign	BRCA1-related condition	2021-04-19	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Fulgent Genetics, Fulgent Genetics	RCV002477030	SCV000575706	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2021-08-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000047608	SCV000576445	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000249365	SCV000602730	likely benign	not specified	2017-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131329	SCV000682991	likely benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000047608	SCV000839279	likely benign	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679684	SCV000888852	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769722	SCV000901143	likely benign	Breast and/or ovarian cancer	2017-08-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000031011	SCV001140594	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047608	SCV002025978	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000249365	SCV002065577	likely benign	not specified	2020-09-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131329	SCV002538055	likely benign	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000249365	SCV004242840	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031011	SCV000053604	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031011	SCV000144201	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679684	SCV001549176	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Ser616del variant is an in-frame deletion resulting in the removal of a serine (Ser) residue at position 616; the impact of this alteration on BRCA1 protein function is not known. It has been identified in the literature in 9 of 6508 proband chromosomes (frequency: 0.001) from Nigerian, Sudanese, Moroccan, British and African- American individuals with breast cancer and HBOC and was present in 3 of the 506 control chromosomes (frequency: 0.006) from healthy individuals (Fackenthal 2012, Biunno 2014, Borg 2010, Ellis 2000, Judkins 2005a, McKean-Cowdin 2005, Tazzite 2012). The variant was identified in control databases in 103 of 282534 chromosomes (0 homozygous) at a frequency of 0.0003646, and was observed at the highest frequency in the African population in 97 of 24900 chromosomes (freq: 0.003896) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was identified in ClinVar (Benign, reviewed by expert panel. Classified as benign by ENIGMA, Ambry Genetics, Michigan Medical Genetics Laboratories, Quest Diagnostics, Invitae, SCRP. Classified as likely benign by ARUP Laboratories, GeneDx, Michigan Medical Genetics Laboratories, Mendelics, CHEO, Color, Institute for Biomarker Research Medical Diagnostic Laboratories, Prevention Genetics, Quest Diagnostics. Classified as VUS by Fulgent, BIC). The variant was also identified in dbSNP (ID: rs rs80358329), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic based on a publication from 2000), and UMD (3X with “unclassified variant” classification). Myriad classifies this as a polymorphism (personal communication). The variant was identified with a co-occurring pathogenic BRCA1 variant (1755del19), increasing the likelihood that the p.Ser616del variant does not have clinical significance (Judkins 2005). The deletion variant localizes to a highly conserved region that interacts with several regulating proteins, however, it was found to occur in both affected and unaffected siblings in an African-American sibship (McKean-Cowdin 2005), but was not identified in controls in a British study looking at BRCA1 mutations in early onset/no family history of breast/ovarian cancer cases (Ellis 2000). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.