ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.696C>A (p.Ser232Arg) (rs201845548)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115322 SCV000149231 uncertain significance not provided 2014-02-18 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.696C>A at the cDNA level, p.Ser232Arg (S232R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Ser232Arg was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a neutral polar amino acid is replaced with a positive polar one, altering a position that is only moderately conserved throughout evolution and is not located in a known functional domain (UniProt). 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.
Illumina Clinical Services Laboratory,Illumina RCV000326657 SCV000394411 uncertain significance Bloom syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000326657 SCV000623347 uncertain significance Bloom syndrome 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 232 of the BLM protein (p.Ser232Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs201845548, ExAC 0.005%). This variant has not been reported in the literature in individuals with BLM-related disease. ClinVar contains an entry for this variant (Variation ID: 127514). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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