ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2839A>G (p.Ile947Val) (rs189925962)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541196 SCV000623292 likely benign Bloom syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016575 SCV001177541 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing Insufficient evidence
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030457 SCV001193517 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000541196 SCV001273602 uncertain significance Bloom syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV001194357 SCV001363843 uncertain significance not specified 2019-07-26 criteria provided, single submitter clinical testing Variant summary: BLM c.2839A>G (p.Ile947Val) results in a conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251454 control chromosomes, predominantly at a frequency of 0.0027 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the expected maximum for a pathogenic variant in BLM causing Bloom Syndrome (0.0035), allowing no conclusion about variant significance. However, the variant was found in certain East Asian subpopulations with higher frequencies, e.g. in the Japanese (0.0076; HGVD), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2839A>G has been reported in the literature in a Korean patient with AML (Kim_2019) and in 8/829 Chinese breast cancer patients (Zhang_2019), but has not to our knowledge been reported in patients with Bloom Syndrome. These reports therefore do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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