ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5428G>A (p.Val1810Ile) (rs80358766)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214539 SCV000274978 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077352 SCV000146613 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000214539 SCV000906816 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000077352 SCV000488153 uncertain significance Breast-ovarian cancer, familial 2 2016-02-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000219100 SCV000591967 uncertain significance not specified 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000589093 SCV000279387 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5428G>A at the cDNA level, p.Val1810Ile (V1810I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 5656G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val1810Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Val1810Ile is located in the RAD51 binding domain (Roy 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Val1810Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589093 SCV000694869 uncertain significance not provided 2017-04-27 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5428G>A (p.Val1810Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 2/121162 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has not been reported in HBOC spectrum patients in the literature, but has been reported in BIC and UMD with a classification of "Uncertain Significance. Following its previous classification as a VUS by our laboratory, this variant has co-occured with a likely pathogenic variant (MSH6 c.3261dupC; p.Phe1088fsX5) in an internal specimen tested at our laboratory and with a pathogenic variant BRCA1 c.1961_1962insA; p.Lys654fsX47 in BIC, suggesting an alternative molecular basis for disease in patients with this variant. This provides additional support in favor of a normal (benign) outcome. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information, control prevalence, and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS)-possibly benign.
Invitae RCV000044658 SCV000072671 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1810 of the BRCA2 protein (p.Val1810Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs80358766, ExAC 0.01%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of the individuals, a pathogenic allele was also identified in BRCA1, which suggests that this c.5428G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51860). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
PreventionGenetics RCV000589093 SCV000805724 uncertain significance not provided 2017-02-21 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077352 SCV000109149 pathogenic Breast-ovarian cancer, familial 2 2012-07-06 no assertion criteria provided clinical testing

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