Submissions for variant NM_007294.4(BRCA1):c.2747A>T (p.Asn916Ile)

gnomAD frequency: 0.00001  dbSNP: rs864622588

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205469	SCV000261220	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 916 of the BRCA1 protein (p.Asn916Ile). 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: 220573). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000218038	SCV000276430	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	clinical testing	The p.N916I variant (also known as c.2747A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2747. The asparagine at codon 916 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000409651	SCV000489323	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001562678	SCV001785482	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218038	SCV003849375	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Color Diagnostics, LLC DBA Color Health	RCV000218038	SCV004360257	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 916 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.