ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9472A>G (p.Thr3158Ala)

gnomAD frequency: 0.00001  dbSNP: rs786204284
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572867 SCV000661236 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-08 criteria provided, single submitter clinical testing The p.T3158A variant (also known as c.9472A>G), located in coding exon 24 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9472. The threonine at codon 3158 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration was also identified in an individual who met criteria for hereditary breast and/or ovarian cancer syndrome (Oliver J et al. Front Oncol, 2019 Dec;9:1429). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other 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.
GeneKor MSA RCV000572867 SCV000821950 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000572867 SCV000903468 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-29 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 3158 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary cancer family (PMID: 31159747). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779966 SCV000916931 uncertain significance not specified 2019-11-21 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9472A>G (p.Thr3158Ala) results in a non-conservative amino acid change located in the BRCA2, OB3 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 251246 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9472A>G has been reported in the literature (Tsaousis_2019). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant once as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000980470 SCV001128424 likely benign Hereditary breast ovarian cancer syndrome 2024-01-20 criteria provided, single submitter clinical testing
GeneDx RCV001564816 SCV001788039 uncertain significance not provided 2019-04-19 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31159747)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001564816 SCV004220658 uncertain significance not provided 2023-09-06 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in at least one individual with hereditary breast and/or ovarian cancer (PMID: 31921681 (2019)). The frequency of this variant in the general population, 0.0000066 (1/152210 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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