ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1561G>A (p.Ala521Thr) (rs80357122)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195389 SCV000075536 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 521 of the BRCA1 protein (p.Ala521Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs80357122, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer (PMID: 17221156, 12491487). ClinVar contains an entry for this variant (Variation ID: 54291). 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 threonine 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. 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 RCV000130445 SCV000185309 likely benign Hereditary cancer-predisposing syndrome 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
GeneDx RCV000586560 SCV000210104 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1561G>A at the cDNA level, p.Ala521Thr (A521T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Using alternate nomenclature, this variant has been previously published as BRCA1 1680G>A. This variant has been reported as a variant of unknown significance in one African-American individual with breast cancer and in two affected individuals from Sicilian hereditary breast/ovarian cancer families, one of whom was diagnosed with male breast cancer (Olopade 2003, Russo 2007). BRCA1 Ala521Thr was also identified in 1/86 healthy African individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA1 Ala521Thr was observed at an allele frequency of 0.06% (15/24,004) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interact with multiple 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 Ala521Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000111646 SCV000488128 uncertain significance Breast-ovarian cancer, familial 1 2016-02-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120288 SCV000600257 uncertain significance not specified 2016-08-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120288 SCV000698875 uncertain significance not specified 2019-05-06 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1561G>A (p.Ala521Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250464 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.1561G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (Olopade_2003, Russo_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four submitters classified the variant as uncertain significance while one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000130445 SCV000903013 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
ITMI RCV000120288 SCV000084440 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111646 SCV000144131 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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