ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.842A>C (p.His281Pro) (rs202042636)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656780 SCV000149234 uncertain significance not provided 2014-01-21 criteria provided, single submitter clinical testing Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.842A>C at the cDNA level, p.His281Pro (H281P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM His281Pro was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral non-polar one, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Invitae RCV000465275 SCV000543345 uncertain significance Bloom syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 281 of the BLM protein (p.His281Pro). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is present in population databases (rs202042636, ExAC 0.02%). This variant has not been reported in the literature in individuals with a BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127517). 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, but 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.
Ambry Genetics RCV000561026 SCV000672889 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000465275 SCV000896479 uncertain significance Bloom syndrome 2018-10-31 criteria provided, single submitter clinical testing
ITMI RCV000120242 SCV000084390 not provided not specified 2013-09-19 no assertion provided reference population

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