ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5497G>A (p.Val1833Met) (rs80357268)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132307 SCV000187393 likely pathogenic Hereditary cancer-predisposing syndrome 2016-03-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA1) RCV000077626 SCV000145548 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000049017 SCV000591635 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000255915 SCV000322039 likely pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5497G>A at the cDNA level, p.Val1833Met (V1833M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant, also published as BRCA1 5616G>A using alternate nomenclature, has been reported in association with breast and ovarian cancer (Ladopoulou 2002, Pal 2005, Stavropoulou 2013). While BRCA1 Val1833Met has been associated with binding activity similar to wild type, functional assays also report it significantly reduces, but does not destroy, transactivation activity in both yeast and human embryonic cell models, mildly to severely impacts protein thermostability, and abrogates the small colony phenotype in yeast (Coyne 2004, Nikolopoulos 2007, Carvalho 2009, Lee 2010, Rowling 2010). BRCA1 Val1833Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val1833Met occurs at a position that is conserved in mammals and is located within the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Val1833Met to be a likely pathogenic variant.
GeneKor MSA RCV000049017 SCV000693500 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049017 SCV000699266 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-03-28 criteria provided, single submitter clinical testing Variant Summary: Variant affects a conserved nucleotide and results in replacement of a medium size and hydrophobic Valine (V) with a medium size and hydrophobic Methionine (M). 4/5 in silico tool predict deleterious outcome for this change. The variant is absent in the large and broad cohorts of the NHLBI-ES and ExAC projects but has been observed in both sporadic and familial HBOC spectrum patients. In one Greek family the variant co-segregated with the disease (Stavropoulou_BRCA1&2_PlosOne_2013) supporting a pathogenic nature for variant. In agreement with a pathogenic impact for the variant functional studies showed that the variant abolishes the transcriptional activity of BRCA1 and destabilizes the protein (Lee_CR_2010, Rowling_JBC_2010). Reputable databases and clinical diagnostic centers classify variant as Likely Pathogenic/Pathogenic. Considering all evidences the variant was classified as likely pathogenic.
Invitae RCV000049017 SCV000077030 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1833 of the BRCA1 protein (p.Val1833Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals and families with breast and/or ovarian cancer, with evidence of segregation with disease in a single family (PMID: 23536787, 12142080, 16284991). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). It is also known as 5616G>A in the literature. ClinVar has an entry for this variant (Variation ID: 55598). This variant is located within the BRCT domain that is important for BRCA1 function. Experimental studies have shown that this missense change affects protein folding and stability, as well as functional activity of the BRCA1 protein (PMID: 20526115, 18992264, 20378548, 15004537, 28781887), while binding specificity to phosphopeptides required for structural integrity is preserved (PMID: 17493881, 20516115). For these reasons, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077626 SCV000296422 likely pathogenic Breast-ovarian cancer, familial 1 2016-05-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077626 SCV000109429 pathogenic Breast-ovarian cancer, familial 1 2012-10-15 no assertion criteria provided clinical testing

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