ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.715G>A (p.Asp239Asn) (rs200756519)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570925 SCV000672948 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000472713 SCV000788545 uncertain significance Bloom syndrome 2017-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000656778 SCV000149232 uncertain significance not provided 2014-01-22 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.715G>A at the cDNA level, p.Asp239Asn (D239N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Asp239Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a negative polar amino acid is replaced with a neutral polar one, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider BLM Asp239Asn 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.
ITMI RCV000120240 SCV000084388 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000472713 SCV000543392 uncertain significance Bloom syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 239 of the BLM protein (p.Asp239Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200756519, ExAC 0.06%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127515). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

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