ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1243G>A (p.Val415Ile) (rs587782770)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132298 SCV000187383 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000167938 SCV000218586 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 415 of the BRCA1 protein (p.Val415Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587782770, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 25971625). ClinVar contains an entry for this variant (Variation ID: 142855). 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 RCV000479340 SCV000296369 uncertain significance not specified 2016-09-07 criteria provided, single submitter clinical testing
Counsyl RCV000238907 SCV000489338 uncertain significance Breast-ovarian cancer, familial 1 2016-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000588638 SCV000565925 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1243G>A at the cDNA level, p.Val415Ile (V415I) 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 BRCA1 1362G>A. This variant has been observed in at least one individual with triple negative breast cancer (Muendlein 2015). BRCA1 Val415Ile was observed at an allele frequency of 0.03% (9/25,778) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val415Ile is located in a region known to interact with multiple proteins (Paul 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 BRCA1 Val415Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588638 SCV000698839 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1243G>A (p.Val415Ile) variant involves the alteration of a non-conserved nucleotide. It is located in serine rich (SR) domain of the protein (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/121228 control chromosomes from ExAC at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been reported in a triple negative breast cancer case who had negative family history of the breast or ovarian cancer (Muendlein_2015). It has also been reported in a database (UMD) four times without co-occurrence with other deleterious variants in BRCA1/2 genes. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Based on the currently available data, this variant has been classified as a Variant of Unknown Significance.
Color RCV000132298 SCV000910915 likely benign Hereditary cancer-predisposing syndrome 2017-08-21 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761081 SCV000890996 uncertain significance Ganglioneuroblastoma 2016-07-22 no assertion criteria provided clinical testing

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