Submissions for variant NM_007294.4(BRCA1):c.3359T>A (p.Val1120Asp)

gnomAD frequency: 0.00001  dbSNP: rs1361427704

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579400	SCV000683100	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588904	SCV000699025	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3359T>A (p.Val1120Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC (0/121134 control chromosomes). In the literature, the variant has been identified in a French family with breast and/or ovarian cancer without strong evidence for or against pathogenicity (Anczukow_Genes Chromosomes and Cancer_2008). Taken together, this variant is classified as VUS until additional evidence becomes available.
Invitae	RCV001035931	SCV001199271	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1120 of the BRCA1 protein (p.Val1120Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18273839). ClinVar contains an entry for this variant (Variation ID: 489715). 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	RCV000579400	SCV002607258	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-22	criteria provided, single submitter	clinical testing	The p.V1120D variant (also known as c.3359T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 3359. The valine at codon 1120 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000579400	SCV003852031	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).
Myriad Genetics, Inc.	RCV003316752	SCV004018679	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].