Submissions for variant NM_007294.4(BRCA1):c.4812A>G (p.Gln1604=)

gnomAD frequency: 0.00064  dbSNP: rs28897693

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112404	SCV000577999	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0043 (South Asian), derived from ExAC (2014-12-17).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084068	SCV000076678	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000112404	SCV000153995	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-01-02	criteria provided, single submitter	literature only
GeneDx	RCV000168511	SCV000167311	benign	not specified	2013-10-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000162689	SCV000213143	likely benign	Hereditary cancer-predisposing syndrome	2014-07-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Baylor Genetics	RCV000471716	SCV000540970	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000585287	SCV000602733	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162689	SCV000683217	benign	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585287	SCV000692907	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BRCA1: BP4, BP7, BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112404	SCV000743388	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-12-29	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112404	SCV000744608	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000585287	SCV000806960	likely benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000112404	SCV001280754	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-04-28	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	RCV001170591	SCV001333179	likely benign	Breast and/or ovarian cancer	2023-04-13	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001084068	SCV002025928	benign	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000168511	SCV002065780	likely benign	not specified	2019-10-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162689	SCV002537784	benign	Hereditary cancer-predisposing syndrome	2020-10-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168511	SCV002550963	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001084068	SCV002761646	benign	Hereditary breast ovarian cancer syndrome	2020-11-24	criteria provided, single submitter	clinical testing	The BRCA1 c.4812A>G variant is classified as Benign (BS1, BP6_Strong, BP4) This BRCA1 c.4812A>G variant is synonymous (silent). The frequency of this variant in population databases is higher than expected for this disorder (BS1). Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported in dbSNP (rs28897693) and has been reported as Benign by other diagnostic laboratories (ClinVar Variation ID: 55293). It has not been reported in HGMD. literature: Seen in 7 patients with breast cancer (Borg et al., 2010 PMID: 20104584).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112404	SCV000145186	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000168511	SCV000591539	benign	not specified		no assertion criteria provided	clinical testing	The BRCA1 p.Gln1604Gln variant was identified in 4 of 2576 proband chromosomes (frequency: 0.001) from Danish, Korean, and American individuals or families with breast and ovarian cancers, and was identified in 5 of 7138 (freq. 0.001) control chromosomes from healthy individuals (Bergthorsson 2001, Kim 2006, McKean-Cowdin 2005). The variant was identified in dbSNP (ID: rs28897693) as “Other”, Fanconi Anemia Mutation Database-LOVD (8x as unknown or unclassified), the ClinVar and Clinvitae databases (conflicting interpretations, classification benign by GeneDx and Invitae, likely benign by Counsyl, Ambry Genetics, and CHEO, and uncertain significance by BIC), GeneInsight COGR database (4x, classified as benign and likely benign by clinical laboratories), the BIC database (4x with unknown clinical importance, classification pending), and UMD (89x with a “likely neutral” classification). In UMD the variant was identified with co-occurring pathogenic BRCA1 variants (c.4065_4068delTCAA, p.Asn1355LysfsX10 and c.68_69delAG, p.Glu23ValfsX17), and BRCA2 variant (c.3847_3848delGT, p.Val1283LysfsX2), increasing the likelihood that the p.Gln1604Gln variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), and HAPMAP-SAS in 5 of 978 chromosomes (frequency: 0.005); the NHLBI GO Exome Sequencing Project in 12 of 8600 European American alleles and in 6 of 4406 African American alleles; the genome Aggregation Database (February 27, 2017) in 294 (5 homozygous) of 282582 chromosomes (freq. 0.001); and the Exome Aggregation Consortium database (August 8th 2016) in 156 (2 homozygous) of 121402 chromosomes (freq. 0.001) in the following populations: Other in 5 of 908 chromosomes (freq. 0.006), South Asian in 71 of 16512 chromosomes (freq. 0.004), European (Non-Finnish) in 67 of 66738 chromosomes (freq. 0.001), African in 7 of 10406 chromosomes (freq. 0.0006), and East Asian in 4 of 8654 chromosomes (freq. 0.0005), Latino in 2 of 11570 chromosomes (freq. 0.0002) but was not seen in Finnish population; increasing the likelihood this could be a low frequency benign variant. The variant was (also) identified by our laboratory in 1 individual with breast cancer. The p.Gln1604Gln 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. In addition, only 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. 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	RCV000112404	SCV000733605	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162689	SCV000805233	likely benign	Hereditary cancer-predisposing syndrome	2018-04-25	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000585287	SCV001798170	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000168511	SCV001906433	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000168511	SCV001954866	benign	not specified		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112404	SCV004243972	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing