ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5497G>A (p.Val1833Met) (rs80357268)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049017 SCV000077030 pathogenic Hereditary breast and ovarian cancer syndrome 2019-09-18 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 and segregated with disease in several families (PMID: 23536787, 12142080, 16284991, Invitae). 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, 30209399), while binding specificity to phosphopeptides required for structural integrity is preserved (PMID: 17493881, 20516115). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000132307 SCV000187393 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing 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
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
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.
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
GeneKor MSA RCV000049017 SCV000693500 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Valine with Methionine at codon 1833 of the BRCA1 protein. The Valine residue is highly conserved among species and it is located within the BRCT domain that is important for BRCA1 function. There is a small physiochemical difference between Valine and Methionine (Grantham Score 21). This variant is also known as 5616G>A and it has been reported in the literature in individuals and families with breast and/or ovarian cancer, with some evidence of segregation with disease in a single family (PMID: 23536787, 12142080). To our Knowledge, this variant is not present in population databases (rs80357268). The mutation database ClinVar contains entries for this variant (Variation ID: 55598). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant may be damaging to the protein. These predictions have been also confirmed by published functional studies. Experimental studies have shown that this missense change affects protein folding and stability, as well as functional activity of the BRCA1 protein (PMID: 18992264, 20378548).
Integrated Genetics/Laboratory Corporation of America RCV000049017 SCV000699266 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-10 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5497G>A (p.Val1833Met) results in a conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several in silico studies also predict a deleterious outcome for the variant (Carvalho_2009, Karchin_2007, Pavlicek_2004, Zhang_1998). Functional studies are in agreement with these predictions demonstrating that although the variant confers normal binding activity, it results in considerably reduced transcriptional activity and destabilizes the protein (Carvalho_2009, Fernandes_2019, Lee_2010, Rowling_2010, Woods_2016). The variant allele was found at a frequency of 4e-06 in 251228 control chromosomes (gnomAD). c.5497G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, including at least one family with evidence of co-segregation with disease (Fostira_2019, Judkins_2005, Kotoula_2017, Pal_2005, Stavropoulou_2013). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000132307 SCV001355748 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-19 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000077626 SCV000145548 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077626 SCV001243464 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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