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 2020-07-28 criteria provided, single submitter clinical testing The p.A469T variant (also known as c.1405G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1405. The alanine at codon 469 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000587317 SCV000293744 uncertain significance not provided 2020-06-29 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28726806)
Invitae RCV000526449 SCV000635795 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-15 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236685 SCV000698861 uncertain significance not specified 2020-11-02 criteria provided, single submitter clinical testing Variant summary: 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 251154 control chromosomes. 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 Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.3599_3600delGT, p.Asp1199_Cys1200insTer), providing supporting evidence for a benign role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4). 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 Health, Inc 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000030992 SCV000591329 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Ala469Thr variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, or BIC databases. The variant was classified as a variant with uncertain significance by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Ala469Thr residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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