ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1405G>A (p.Ala469Thr) (rs397507187)

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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 RCV000165869 SCV000216618 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000587317 SCV000293744 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1405G>A at the cDNA level, p.Ala469Thr (A469T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Using alternate nomenclature, this variant would be defined as BRCA1 1524G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala469Thr 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 Ala469Thr occurs at a position that is not conserved and is located in the DNA binding domain and in a region known to interact with multiple other proteins, including MB1, RAD50, p53, ZBRK1, GADD45, and BRG1 (Wang 1998, Zhang 1998, Chai 1999, Zhong 1999, Narod 2004, Harte 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ala469Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236685 SCV000591329 uncertain significance not specified 2014-10-24 criteria provided, single submitter clinical testing
Invitae RCV000526449 SCV000635795 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 469 of the BRCA1 protein (p.Ala469Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. 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: 37411). 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 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.
Integrated Genetics/Laboratory Corporation of America RCV000236685 SCV000698861 uncertain significance not specified 2019-01-30 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.1405G>A (p.Ala469Thr) results in a non-conservative amino acid change located in the BRCA1, serine-rich domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245946 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1405G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587317 SCV000887623 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing
Color RCV000165869 SCV000911274 likely benign Hereditary cancer-predisposing syndrome 2017-01-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000030992 SCV000053584 uncertain significance Breast-ovarian cancer, familial 1 2009-05-06 no assertion criteria provided clinical testing

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