Submissions for variant NM_007294.4(BRCA1):c.548-3T>C

gnomAD frequency: 0.00001  dbSNP: rs397507252

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473116	SCV000549346	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 37677). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000482750	SCV000571757	uncertain significance	not provided	2016-09-23	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.548-3T>C or IVS7-3T>C and consists of a T>C nucleotide substitution at the -3 position of intron 7 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 667-3T>C. In silico models are inconclusive with respect to splicing, and in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 c.548-3T>C was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is not conserved across species. Based on currently available evidence, it is unclear whether BRCA1 c.548-3T>C is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000031258	SCV000786141	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-03-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771276	SCV000903423	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771276	SCV001186134	likely benign	Hereditary cancer-predisposing syndrome	2019-10-11	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482750	SCV004219464	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/250806 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRCA1 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000031258	SCV004821663	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-02-24	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031258	SCV000053862	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-05-24	no assertion criteria provided	clinical testing