ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.22G>A (p.Val8Ile) (rs528902306)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589934 SCV000292500 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.22G>A at the cDNA level, p.Val8Ile (V8I) 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 141G>A. This variant has been reported in at least one individual with breast cancer (Tung 2015). BRCA1 Val8Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Val8Ile is located in the RING domain and a region known to interact with multiple other proteins (Borg 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Val8Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573882 SCV000661050 likely benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000589934 SCV000698937 uncertain significance not provided 2017-07-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.22G>A (p.Val8Ile) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120750 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant was found in one breast cancer patient in literature without strong evidence for or against pathogenicity (Tung_2015). In addition, one clinical diagnostic laboratory (via ClinVar) and one database (UMD) have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance.
Color RCV000573882 SCV000909430 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
Invitae RCV000816431 SCV000956940 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-08 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 8 of the BRCA1 protein (p.Val8Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with breast cancer (PMID: 25186627, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.22G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 243118). 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.

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