Submissions for variant NM_007294.4(BRCA1):c.736T>G (p.Leu246Val)

gnomAD frequency: 0.00026  dbSNP: rs28897675

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)	RCV000112779	SCV000244410	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 = 0.000000531
Invitae	RCV000049113	SCV000077126	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034762	SCV000167234	benign	not provided	2018-11-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27153395, 22703879, 24055113, 19200354, 23867111, 21520273, 25637381, 21990134, 25782689, 15235020, 16014699, 21965345, 15307796, 15300854, 25823446, 26246475, 26332594, 33087888)
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112779	SCV000195886	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162555	SCV000212965	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.
Counsyl	RCV000112779	SCV000220389	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-06-08	criteria provided, single submitter	literature only
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000049113	SCV000267857	likely benign	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148400	SCV000324818	likely benign	Breast and/or ovarian cancer	2022-11-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157724	SCV000538445	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD in 1 individual, showing that it leads to loss of expression of BRCA1. This variant is present in ExAC with a Max MAF of 0.04% (25/65600 chrs). It is classified in ClinVar with 3 stars as benign by 5 submitters (including expert panel ENIGMA), Likely benign by 3 submitters, and VUS by 3 submitters.
Genetic Services Laboratory, University of Chicago	RCV000157724	SCV000593663	likely benign	not specified	2016-07-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034762	SCV000602736	benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162555	SCV000683352	benign	Hereditary cancer-predisposing syndrome	2015-01-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000112779	SCV001140623	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112779	SCV001280988	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-27	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000148400	SCV001333444	likely benign	Breast and/or ovarian cancer	2021-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034762	SCV001501183	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BRCA1: BP1, BS3:Supporting
Sema4, Sema4	RCV000162555	SCV002537895	likely benign	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000157724	SCV002551042	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504870	SCV002808838	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2022-03-22	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034762	SCV000043184	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112779	SCV000145673	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148400	SCV000190099	uncertain significance	Breast and/or ovarian cancer	2014-06-01	no assertion criteria provided	research
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000112779	SCV000493711	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-06-04	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353473	SCV000591299	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1, p.Leu246Val variant was identified in 7 of 7716 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Akbari 2011, Capanu 2011, Diez 2003). The variant was also identified in dbSNP (ID: rs28897675) “With Uncertain significance allele”, with a minor allele frequency of 0.0002 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, LOVD, the ClinVar database (classified as a benign variant by the Invitae, GeneDx and Ambry genetics; classified as Likely benign by Counsyl; classified as Uncertain significance by BIC, by Biesecker Laboratory and by CSER_CC_NCGL), GeneInsight COGR database (1X, classified as “Benign” by a clinical laboratory), the BIC database (80X with unknown clinical importance), and UMD (17X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1 c.3901_3902delAG (p.Ser1301X); BRCA2 c.5984dup (p.Asn1995delinsLys)), increasing the likelihood that the p.Leu246Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), Exome Variant Server project in 3 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 26 of 76950 chromosomes (frequency: 0.0003) from a population of European (Non-Finnish) and Latino individuals, increasing the likelihood this could be a low frequency benign variant. The p.Leu246 residue is not conserved in mammals and four out of five 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. In addition, the Val residue is also present in opossum, which would increase the likelihood this variant may not have functional significance. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. RNA based analysis by Sharp (2004) suggest that the mutation is associated with either constitutive skipping of exon 11, or monoallelic BRCA1 expression. However, two functional studies characterized the variant as neutral (Abkevich 2004, Gómez García 2009). In addition, this variant have been observed with two or more known deleterious mutations, increasing the likelihood this variant does not have clinical significance (Tavtigian 2006, Judkins 2005). 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	RCV000112779	SCV000733666	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000034762	SCV000778774	likely benign	not provided	2017-04-03	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162555	SCV000787913	likely benign	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000148400	SCV000863627	uncertain significance	Breast and/or ovarian cancer	2002-03-15	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000157724	SCV001799917	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000157724	SCV001905687	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000157724	SCV001931498	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000157724	SCV001953037	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000157724	SCV001972436	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112779	SCV004244149	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing