ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1849A>G (p.Thr617Ala) (rs45564238)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130111 SCV000184941 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409706 SCV000487806 uncertain significance Breast-ovarian cancer, familial 1 2015-11-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000416510 SCV000494430 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-01-29 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was detected in controls with allele frequency of 0.000008, which does not exceed the maximal expected frequency for a pathogenic allele (0.0010005). This variant has not been reported, to our knowledge, in affected individuals. Multiple reputable databases/clinical laboratories cite the variant with a classification of "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000416510 SCV000549285 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 617 of the BRCA1 protein (p.Thr617Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. 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: 41807). 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 alanine 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.
GeneDx RCV000034729 SCV000567821 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1849A>G at the cDNA level, p.Thr617Ala (T617A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). Using alternate nomenclature, this variant would be defined as BRCA1 1968A>G. This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). BRCA1 Thr617Ala was not observed in large population cohorts (Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr617Ala 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, support a deleterious effect. Based on currently available information, it is unclear whether BRCA1 Thr617Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034729 SCV000698892 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1849A>G (p.Thr617Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Amongst the ExAC control database and publications, this variant was found in 1/122330 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000130111 SCV000911431 likely benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034729 SCV000043179 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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