Submissions for variant NM_007294.4(BRCA1):c.2167A>G (p.Asn723Asp)

gnomAD frequency: 0.00209  dbSNP: rs4986845

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031035	SCV000244315	benign	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 1 based on posterior probability = 0.000000000317
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167793	SCV000075752	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001703431	SCV000167251	benign	not provided	2018-11-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24055113, 24729269, 25637381, 21990134, 15235020, 15447980, 27153395, 26332594, 16267036, 17924331, 22811390, 25948282, 22753008, 12491487, 33087888)
CSER _CC_NCGL, University of Washington	RCV000148398	SCV000190097	likely benign	Malignant tumor of prostate	2014-06-01	criteria provided, single submitter	research
Ambry Genetics	RCV000162975	SCV000213463	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: 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.
Counsyl	RCV000031035	SCV000220269	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-04-25	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000173845	SCV000225006	likely benign	not specified	2016-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167793	SCV000494350	benign	Hereditary breast ovarian cancer syndrome	2014-02-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000167793	SCV000576444	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162975	SCV000683016	likely benign	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000173845	SCV000806911	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000031035	SCV001140581	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031035	SCV001283973	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001703431	SCV001477835	benign	not provided	2023-09-19	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000167793	SCV002025986	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173845	SCV002070444	likely benign	not specified	2021-10-01	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000167793	SCV002515189	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162975	SCV002538099	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173845	SCV002551022	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000031035	SCV002556920	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2021-08-24	criteria provided, single submitter	clinical testing	The BRCA1 c.2167A>G variant is classified as Benign (BS1, BS4, BP4, BP6)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031035	SCV004016779	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031035	SCV004818220	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031035	SCV000053629	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2008-08-11	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031035	SCV000144316	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000173845	SCV000587192	benign	not specified	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353651	SCV000591371	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asn723Asp variant was identified in an individual with hereditary prostate cancer (Zuhlke 2004), and in at least 20 other patients from a data set 55630 patients undergoing clinical BRCA1 mutation screening (Judkins 2005). The variant was also identified in HGMD, LOVD, the BIC database (26X with unknown clinical importance), and UMD (6X as a neutral variant). In UMD the variant was listed once as co-occurring with a known pathogenic mutation in BRCA1 (c.-200_80del (p.Met1SerfsX13)), and Judkins (2005) identified the variant in trans with a different pathogenic BRCA1 mutation (p.Cys64Tyr), increasing the likelihood that the p.Asn723Asp variant does not have clinical importance. This residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Three in silico studies suggest that the variant is not pathogenic or of no clinical significance (Abkevich 2004, Easton 2007, Lindor 2012). The variant was listed in dbSNP (ID: rs4986845) “With non-pathogenic allele”, with a minor allele frequency of 0.002 (1000 Genomes Project). It was also identified in the NHLBI Exome Sequencing Project with a frequency of 0.007 in African American alleles, and in several HapMap populations including HAPMAP-MKK (frequency: 0.014), HAPMAP-LWK (frequency: 0.011) and HAPMAP-ASW (frequency: 0.01), increasing the likelihood that this is a low frequency benign polymorphism in certain populations of origin. 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.
True Health Diagnostics	RCV000162975	SCV000787896	likely benign	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735455	SCV000863592	likely benign	Breast and/or ovarian cancer	2013-09-16	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000173845	SCV001905792	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000173845	SCV001958610	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031035	SCV004244100	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing