Submissions for variant NM_007294.4(BRCA1):c.114G>A (p.Lys38=)

gnomAD frequency: 0.00233  dbSNP: rs1800062

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111799	SCV000244845	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-01-12	reviewed by expert panel	curation	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.05769 (Asian), derived from 1000 genomes (2012-04-30).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000047360	SCV000075373	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000111799	SCV000154026	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-03-13	criteria provided, single submitter	literature only
Ambry Genetics	RCV000162531	SCV000212930	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.
Illumina Laboratory Services, Illumina	RCV000111799	SCV000403076	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	RCV000047360	SCV000494301	benign	Hereditary breast ovarian cancer syndrome	2014-02-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474769	SCV000540973	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000496808	SCV000586864	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656647	SCV000602711	benign	not provided	2023-11-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162531	SCV000682939	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000496808	SCV000693597	benign	not specified	2017-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000496808	SCV000806892	benign	not specified	2017-06-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000496808	SCV001470156	benign	not specified	2020-06-15	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656647	SCV002009475	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000047360	SCV002026043	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000047360	SCV002515198	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000162531	SCV002537999	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000496808	SCV002551074	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149698	SCV003838913	benign	Breast and/or ovarian cancer	2021-11-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656647	SCV004699820	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BP7, BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000656647	SCV005251101	benign	not provided		criteria provided, single submitter	not provided
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111799	SCV000144344	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2006-07-19	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000111799	SCV000189325	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2011-03-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000496808	SCV000591239	benign	not specified		no assertion criteria provided	clinical testing	The BRCA1 p.Lys38= variant was identified in 16 of 604 proband chromosomes (frequency: 0.026) from Asian and Colombian individuals or families with hereditary breast and/or ovarian cancer or early-onset breast cancer and was present in 3 of 142 control chromosomes (frequency: 0.021) from healthy individuals (Torres_2007_17080309, Ho_2000_10951344, Chen_2003_12602912, Song_2006_16835750, Toh_2008_18431501). The variant was also identified in dbSNP (ID: rs1800062) as “With Uncertain significance, other allele”, ClinVar and Clinvitae (11x classified as benign by ENIGMA, Laboratory Corporation of America, Baylor Miraca Genetics, British Columbia Cancer Agency (COGR), Sinai Health System (COGR), ARUP Laboratories, Invitae, Counsyl, Ambry Genetics, SCRP, BIC; 2x classified as likely benign by Illumina Clinical Services and CHEO), GeneInsight-COGR (classified as likely benign/benign by COGR consensus and Sinai Health System), LOVD 3.0 (11 entries, classified as does not affect function or not classified), UMD-LSDB (37 entries, 2 of which have co-occurring pathogenic variants), BIC Database (18 entries, classified as not pathogenic), and the Zhejiang Colon Cancer Database (5 entries classified as no known pathogenicity). The variant was not identified in the COSMIC, MutDB, or ARUP Laboratories databases. The variant was identified in control databases in 1135 of 276592 chromosomes (18 homozygous) at a frequency of 0.004 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 23984 chromosomes (freq: 0.0002), Other in 13 of 6450 chromosomes (freq: 0.002), Latino in 368 of 34346 chromosomes (freq: 0.01), European Non-Finnish in 2 of 126380 chromosomes (freq: 0.00002), East Asian in 741 of 18846 chromosomes (freq: 0.04), European Finnish in 1 of 25776 chromosomes (freq: 0.00004), and South Asian in 6 of 30688 chromosomes (freq: 0.0002) while the variant was not observed in the Ashkenazi Jewish population. The p.Lys38= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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	RCV000111799	SCV000733682	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656647	SCV000778780	benign	not provided	2016-12-19	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162531	SCV000787892	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111799	SCV001241896	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000496808	SCV001798401	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000496808	SCV001906278	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000656647	SCV001930570	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000496808	SCV001954762	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000496808	SCV001965154	benign	not specified		no assertion criteria provided	clinical testing