ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5122G>A (p.Ala1708Thr) (rs397507243)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198404 SCV000254994 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-05-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1708 of the BRCA1 protein (p.Ala1708Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant has not been published in the literature and is not currently found in any individuals from the population databases (rs397507243, no frequency). ClinVar contains an entry for this variant (RCV000031220). A different missense substitution at this codon (p.Ala1708Val) is reported to be deleterious (PMID: 15923272, 17305420). This indicates that the Ala1708 residue is important for BRCA1 protein function. 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant affects a highly conserved residue that is also altered by a known pathogenic variant. However, there is no functional or segregation evidence to prove that this variant is deleterious. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000223569 SCV000275547 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Well-characterized mutation at same position
Sharing Clinical Reports Project (SCRP) RCV000031220 SCV000053820 uncertain significance Breast-ovarian cancer, familial 1 2012-01-31 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031220 SCV001237648 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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