ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.3874G>A (p.Ala1292Thr)

gnomAD frequency: 0.00001  dbSNP: rs757641454
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001021333 SCV001182936 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-20 criteria provided, single submitter clinical testing The p.A1292T variant (also known as c.3874G>A), located in coding exon 19 of the BLM gene, results from a G to A substitution at nucleotide position 3874. The alanine at codon 1292 is replaced by threonine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 19 and may have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030461 SCV001193521 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Invitae RCV001832350 SCV002173137 uncertain significance Bloom syndrome 2022-08-19 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1292 of the BLM protein (p.Ala1292Thr). This variant also falls at the last nucleotide of exon 20, which is part of the consensus splice site for this exon. This variant is present in population databases (rs757641454, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 824326). 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 tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Natera, Inc. RCV001832350 SCV002090619 uncertain significance Bloom syndrome 2020-11-16 no assertion criteria provided clinical testing

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