ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2528C>T (p.Ala843Val) (rs80358517)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219470 SCV000275168 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000483891 SCV000564770 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2528C>T at the cDNA level, p.Ala843Val (A843V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). Using alternate nomenclature, this variant would be defined as BRCA2 2756C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant; however it has been reported as a somatic variant in an endometrial carcinoma sample according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. BRCA2 Ala843Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ala843Val occurs at a position that is not conserved 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 evidence, it is unclear whether BRCA2 Ala843Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781048 SCV000918828 uncertain significance not specified 2017-10-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2528C>T (p.Ala843Val) variant involves the alteration of a non-conserved nucleotide, leading to an amino acid substitution in a protein region that is not located in any known domain. Since alanine and valine share similar size and physicochemical properties, this substitution is considered a conservative amino acid change. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 273524 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113055 SCV000146062 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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