ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5411T>C (p.Val1804Ala) (rs370252983)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129811 SCV000184625 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129811 SCV000906592 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000624983 SCV000744469 likely benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000766625 SCV000210352 uncertain significance not provided 2014-12-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5411T>C at the cDNA level, p.Val1804Ala (V1804A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val1804Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val1804Ala occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Val1804Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000624983 SCV000743308 likely benign Breast-ovarian cancer, familial 2 2017-07-28 criteria provided, single submitter clinical testing
ITMI RCV000120347 SCV000084499 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000685972 SCV000813474 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-23 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1804 of the BRCA2 protein (p.Val1804Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs370252983, ExAC 0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 17018160, 14722926). ClinVar contains an entry for this variant (Variation ID: 133736). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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