ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.670G>A (p.Ala224Thr) (rs431825419)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164848 SCV000215531 uncertain significance Hereditary cancer-predisposing syndrome 2014-06-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235969 SCV000293477 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.670G>A at the cDNA level, p.Ala224Thr (A224T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 789G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala224Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala224Thr occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant destroys the natural splice donor site for exon/intron 9 and leads to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA1 Ala224Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000083075 SCV000487930 uncertain significance Breast-ovarian cancer, familial 1 2015-12-04 criteria provided, single submitter clinical testing
Invitae RCV000637680 SCV000759150 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 224 of the BRCA1 protein (p.Ala224Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 9 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. 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 disease. ClinVar contains an entry for this variant (Variation ID: 96954). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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 and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional 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.
Sharing Clinical Reports Project (SCRP) RCV000083075 SCV000115149 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing

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