ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5422G>T (p.Val1808Leu)

dbSNP: rs1555574756
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580194 SCV000683313 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-25 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 1808 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.
Invitae RCV000804227 SCV000944124 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-13 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 1808 of the BRCA1 protein (p.Val1808Leu). 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: 489731). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV000580194 SCV002647929 likely benign Hereditary cancer-predisposing syndrome 2020-03-25 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV003478305 SCV004175709 uncertain significance Familial cancer of breast 2023-10-23 criteria provided, single submitter clinical testing Heterozygous variant NM_007294:c.5422G>T (p.Val1808Leu) in the BRCA1 gene was found on WES data in female proband (45 y.o., Caucasian) with breast cancer. No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is absent in The Genome Aggregation Database (gnomAD) v2.1.1 and v.3.1.2 (Date of access with 23-10-2023). Clinvar contains an entry for this variant (Variation ID: 489731). This variant has not been reported in any study to our knowledge. Functional analysis of an alternative change c.5422G>C with the same protein change p.Val1808Leu shows normal functioning of the protein (https://sge.gs.washington.edu/BRCA1/). Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: BS3_moderate, PM2.
Baylor Genetics RCV003459418 SCV004215149 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2023-05-01 criteria provided, single submitter clinical testing

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