ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4813G>A (p.Val1605Ile) (rs786201175)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162834 SCV000213320 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000221573 SCV000278853 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4813G>A at the cDNA level, p.Val1605Ile (V1605I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant, also known as BRCA2 5041G>A by alternate nomenclature, has been reported in at least one individual with a history of early onset breast cancer (Maxwell 2015). BRCA2 Val1605Ile was not observed in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val1605Ile is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Val1605Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000162834 SCV000688898 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing
Invitae RCV000637639 SCV000759106 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1605 of the BRCA2 protein (p.Val1605Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 21520333) and individuals at high risk for breast and ovarian cancer (PMID: 18418466). However, in one of these individuals a pathogenic allele were also identified in BRCA1, which suggests that this c.4813G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 183942). 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 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221573 SCV000887827 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing

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