Submissions for variant NM_007294.4(BRCA1):c.3358G>A (p.Val1120Ile)

gnomAD frequency: 0.00001  dbSNP: rs748894760

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163154	SCV000213671	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	clinical testing	The p.V1120I variant (also known as c.3358G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3358. The valine at codon 1120 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this variant was not detected in 60,466 breast cancer cases but reported in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is 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	RCV000200265	SCV000254972	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1120 of the BRCA1 protein (p.Val1120Ile). This variant is present in population databases (rs748894760, gnomAD 0.002%). 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: 184039). 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.
GeneDx	RCV000235337	SCV000293908	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 3477G>A
Counsyl	RCV000410885	SCV000488703	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163154	SCV000688431	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1120 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250270 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.
Sema4, Sema4	RCV000163154	SCV002538201	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163154	SCV003852055	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).
PreventionGenetics, part of Exact Sciences	RCV003952818	SCV004771431	uncertain significance	BRCA1-related condition	2023-12-15	criteria provided, single submitter	clinical testing	The BRCA1 c.3358G>A variant is predicted to result in the amino acid substitution p.Val1120Ile. To our knowledge, this variant has not been reported in the literature in individuals with BRCA1-related disorders. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184039/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.