Submissions for variant NM_007294.4(BRCA1):c.2077G>A (p.Asp693Asn)

gnomAD frequency: 0.05782  dbSNP: rs4986850

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111758	SCV000244313	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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), 0.08443 (European), derived from 1000 genomes (2012-04-30).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047702	SCV000075715	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000111758	SCV000154007	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-02	criteria provided, single submitter	literature only	High frequency in a 1kG or ESP population: 7.0 %.
GeneDx	RCV000157727	SCV000167248	benign	Familial cancer of breast	2013-09-03	criteria provided, single submitter	clinical testing	The variant is found in BRCA1-BRCA2 panel(s).
Ambry Genetics	RCV000129094	SCV000183805	benign	Hereditary cancer-predisposing syndrome	2014-10-29	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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000111758	SCV000195899	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120289	SCV000202272	benign	not specified	2015-03-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129094	SCV000292092	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120289	SCV000311787	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000111758	SCV000403068	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047702	SCV000494306	benign	Hereditary breast ovarian cancer syndrome	2014-11-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000157727	SCV000540960	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000120289	SCV000586880	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034730	SCV000602670	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000120289	SCV000693604	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000111758	SCV000743421	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000111758	SCV000744666	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047702	SCV002025993	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000047702	SCV002515186	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000129094	SCV002538087	benign	Hereditary cancer-predisposing syndrome	2020-01-10	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496521	SCV002809237	benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-23	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000111758	SCV004016749	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	RCV000111758	SCV004818226	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034730	SCV005251071	benign	not provided		criteria provided, single submitter	not provided
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034730	SCV000043178	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000120289	SCV000084441	not provided	not specified	2013-09-19	no assertion provided	reference population
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111758	SCV000144288	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000111758	SCV000189330	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120289	SCV000591367	benign	not specified		no assertion criteria provided	clinical testing	The BRCA1 p.Asp693Asn variant was identified in the literature and was also identified in dbSNP (ID: rs4986850) “With Benign ,untested allele”, with a minor allele frequency of 0.034 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, by Invitae, BIC, Counsy, GeneDX, Ambry Genetics and Biesecker Laboratory ), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “benign” by a clinical laboratory), the BIC database (64X with no clinical importance), and UMD (16X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.IVS22+5G>C (c.5406+5G>C); c.5503C>T (p.Arg1835X); c.3257T>G (p.Leu1086X) BRCA1 and c.6405_6409delCTTAA (p.Asn2135LysfsX3) BRCA2), increasing the likelihood that the p.Asp693Asn variant does not have clinical significance. This variant was also identified in the HAPMAP-CEU in 22 of 226 chromosomes (frequency: 0.097), HAPMAP-YRI in 2 of 226 chromosomes (frequency: 0.009), HAPMAP-MKK in 5 of 286 chromosomes (frequency: 0.017), Exome Variant Server project in 706 of 13004 European American and African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The p.Asp693 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Furthermore, six studies call the variant as polymorphism, neutral or of little clinical significance (Abkevich 2004, Bodian 2014, Feliubadalo 2013, Johnston 2012, Lindor 2012, Tavtigian 2006). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000111758	SCV000733649	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034730	SCV000778763	benign	not provided	2016-12-27	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000129094	SCV000787895	benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120289	SCV001906322	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120289	SCV001955083	benign	not specified		no assertion criteria provided	clinical testing