ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1571C>T (p.Ala524Val) (rs80357333)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047529 SCV000075542 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 524 of the BRCA1 protein (p.Ala524Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs80357333, ExAC 0.002%). This variant has been observed in families and an individual affected with breast and/or ovarian cancer (PMID: 17453335, 18273839, 27498913). ClinVar contains an entry for this variant (Variation ID: 54297). 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.
Ambry Genetics RCV000167144 SCV000217974 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587950 SCV000224990 uncertain significance not provided 2014-09-05 criteria provided, single submitter clinical testing
GeneDx RCV000587950 SCV000293220 uncertain significance not provided 2018-11-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1571C>T at the cDNA level, p.Ala524Val (A524V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant, also defined as BRCA1 1690C>T using alternate nomenclature, has been observed in at least two families with breast and/or ovarian cancer (Anczukow 2008, Konstantopoulou 2008). BRCA1 Ala524Val was not observed in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ala524Val is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, 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 Ala524Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000111648 SCV000489605 uncertain significance Breast-ovarian cancer, familial 1 2016-10-27 criteria provided, single submitter clinical testing
Color RCV000167144 SCV000688343 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587950 SCV000698876 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1571C>T (p.Ala524Val) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120730 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 has been reported in multiple patients without clear evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587950 SCV000887628 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111648 SCV000144134 uncertain significance Breast-ovarian cancer, familial 1 2006-05-05 no assertion criteria provided clinical testing

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