Submissions for variant NM_007294.4(BRCA1):c.5470A>G (p.Ile1824Val)

dbSNP: rs587782026

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130459	SCV000185324	likely benign	Hereditary cancer-predisposing syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168345	SCV000219034	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-11	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). ClinVar contains an entry for this variant (Variation ID: 141804). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1824 of the BRCA1 protein (p.Ile1824Val).
GeneDx	RCV000481196	SCV000566784	uncertain significance	not provided	2017-06-27	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.5470A>G at the cDNA level, p.Ile1824Val (I1824V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 5589A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ile1824Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile1824Val occurs at a position that is not conserved and is located in the BRCT 2 domain as well as a region known to interact with multiple other proteins (UniProt, Paul 2014). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may create a new cryptic splice acceptor site and possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 Ile1824Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130459	SCV000683323	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1824 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). A functional study has reported that this variant protein is functional in a human haploid cell line-based survival assay (PMID: 30209399). To our knowledge, 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.
Fulgent Genetics, Fulgent Genetics	RCV000765356	SCV000896621	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001076289	SCV004215195	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-03-06	criteria provided, single submitter	clinical testing
Brotman Baty Institute, University of Washington	RCV001076289	SCV001242009	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro