Submissions for variant NM_007294.4(BRCA1):c.3346G>C (p.Val1116Leu)

gnomAD frequency: 0.00006  dbSNP: rs55909400

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218827	SCV000273771	likely benign	Hereditary cancer-predisposing syndrome	2019-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000218827	SCV000906683	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 1116 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 been reported in an individual affected with breast cancer (PMID: 15726418). This variant has been identified in 6/281642 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779859	SCV000916724	uncertain significance	not specified	2017-11-16	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3346G>C (p.Val1116Leu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/276252 control chromosomes at a frequency of 0.0000217, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been reported in affected individuals in the literature (Judkins 2005, McKean-Cowdin 2005), but without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae	RCV001319129	SCV001509860	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1116 of the BRCA1 protein (p.Val1116Leu). This variant is present in population databases (rs55909400, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 15726418). ClinVar contains an entry for this variant (Variation ID: 54853). 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	RCV001561298	SCV001783869	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (McKean-Cowdin et al., 2005); Also known as 3465G>C; This variant is associated with the following publications: (PMID: 16267036, 15726418, 29884841, 15385441, 32377563)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001561298	SCV002774456	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (4/24796 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMIDs: 15726418 (2005) and 16267036 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218827	SCV003852143	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).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000112076	SCV004031182	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-15	criteria provided, single submitter	clinical testing	The BRCA1 c.3346G>C (p.Val1116Leu) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with breast cancer (PMID: 15726418). In addition, one individual with this variant was reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003398635	SCV004106011	uncertain significance	BRCA1-related condition	2023-06-09	criteria provided, single submitter	clinical testing	The BRCA1 c.3346G>C variant is predicted to result in the amino acid substitution p.Val1116Leu. This variant was reported in an individual with breast and/or ovarian cancer (Figure 1 in McKean-Cowdin et al. 2005. PubMed ID: 15726418). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41244202-C-G) and has conflicting interpretations in ClinVar regarding its pathogenicity, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/54853/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112076	SCV000144732	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing