Submissions for variant NM_007294.4(BRCA1):c.985A>T (p.Asn329Tyr)

gnomAD frequency: 0.00001  dbSNP: rs786203732

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167164	SCV000217997	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-02	criteria provided, single submitter	clinical testing	The p.N329Y variant (also known as c.985A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 985. The asparagine at codon 329 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is not well 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.
Invitae	RCV000196902	SCV000254999	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 329 of the BRCA1 protein (p.Asn329Tyr). This variant is present in population databases (rs786203732, gnomAD 0.01%). 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: 187436). 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. 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	RCV000759566	SCV000293976	uncertain significance	not provided	2019-08-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as BRCA1 1104A>T
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759566	SCV000888960	uncertain significance	not provided	2018-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167164	SCV000909393	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with tyrosine at codon 329 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been reported in 2 individuals age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/17-41246563-T-A). This variant has been identified in 1/31408 chromosomes 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167164	SCV003846250	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759566	SCV000591312	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Asn329Tyr variant has not been reported in the literature nor previously identified by our laboratory. This residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. It should be noted that BRCA1 variants are inherited in an autosomal dominant manner with reduced penetrance and that the expression of the disease can be influenced by other modifier genes and environmental factors. The significance of a variant should always be interpreted in the context of the individual's clinical manifestations. In addition, genetic counseling is recommended and testing of additional family members may help to understand the significance of this variant.