ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1234G>A (p.Val412Ile) (rs587776478)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159951 SCV000210100 uncertain significance not provided 2014-09-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1234G>A at the cDNA level, p.Val412Ile (V412I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant, also known as BRCA1 c.1353G>A using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val412Ile 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 Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val412Ile occurs at a position that is variable 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 BRCA1 Val412Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165140 SCV000215850 uncertain significance Hereditary cancer-predisposing syndrome 2014-08-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001064185 SCV001229067 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 412 of the BRCA1 protein (p.Val412Ile). The valine residue is moderately 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 not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 156182). 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.
Color RCV000165140 SCV001354416 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000144199 SCV000189272 uncertain significance Breast-ovarian cancer, familial 1 2012-12-15 no assertion criteria provided clinical testing

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