ClinVar Miner

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

dbSNP: rs80357268
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049017 SCV000077030 pathogenic Hereditary breast ovarian cancer syndrome 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1833 of the BRCA1 protein (p.Val1833Met). This variant is present in population databases (rs80357268, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10923033, 12142080, 16284991, 23536787; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 5616G>A. ClinVar contains an entry for this variant (Variation ID: 55598). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15004537, 17493881, 18992264, 20378548, 20516115, 20526115, 28781887, 30209399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000132307 SCV000187393 likely pathogenic Hereditary cancer-predisposing syndrome 2023-05-02 criteria provided, single submitter clinical testing The p.V1833M variant (also known as c.5497G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5497. The valine at codon 1833 is replaced by methionine, an amino acid with highly similar properties. This alteration has been found with enriched frequency in cohorts of Greek breast and/or ovarian cancer patients and segregated with disease in one kindred with familial ovarian cancer (Stavropoulou AV, PLoS ONE 2013; 8(3):e58182; Apessos A et al. Cancer Genet 2018 01;220:1-12; Papamentzelopoulou M et al. Cancer Genet. 2019 Sep;237:90-96). The work by Rowling et al., both experimentally and computationally showed the destabilization of the BRCT2 domain by this variant, significantly leading to unfolding and loss of function (Rowling PJ, J. Biol. Chem. 2010 Jun; 285(26):20080-7). Functional assays demonstrate reduced transactivation activity compared to wild-type (Carvalho M, Mutat. Res. 2009 Jan; 660(1-2):1-11, Woods et al, npj Genomic Medicine 1, Article number: 16001 (2016) doi:10.1038/npjgenmed.2016.1; Findlay GM et al. Nature 2018 10;562(7726):217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077626 SCV000296422 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 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.
GeneKor MSA RCV000049017 SCV000693500 likely pathogenic Hereditary breast 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049017 SCV000699266 pathogenic Hereditary breast ovarian cancer syndrome 2022-11-16 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). At least one functional study reports experimental evidence evaluating an impact on protein function a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. 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. Eight ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000132307 SCV001355748 likely pathogenic Hereditary cancer-predisposing syndrome 2022-10-10 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 1833 of the BRCA1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs BRCA1 protein folding and stability, transcriptional activation, and ability to support haploid cell survival (PMID: 15004537, 17493881, 18992264, 20378548, 20526115, 28781887, 30209399). This variant is known to be a founder mutation in the Greek population (PMID: 31447071) and has been observed in many individuals affected with breast and ovarian cancer (PMID: 16284991, 23536787, 31447071). This variant has also been identified in 1/251228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255915 SCV001447942 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mendelics RCV002247446 SCV002518585 pathogenic Familial cancer of breast 2022-05-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077626 SCV000109429 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2012-10-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077626 SCV000145548 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000255915 SCV000591635 uncertain significance not provided no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000077626 SCV001243464 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
BRCAlab, Lund University RCV000077626 SCV004243906 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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