Submissions for variant NM_000057.4(BLM):c.2422C>T (p.Arg808Cys)

gnomAD frequency: 0.00001  dbSNP: rs759330541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471360	SCV000543323	uncertain significance	Bloom syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 808 of the BLM protein (p.Arg808Cys). This variant is present in population databases (rs759330541, gnomAD 0.007%). This missense change has been observed in individual(s) with early-onset, undefined familial colorectal cancer (PMID: 27356891). ClinVar contains an entry for this variant (Variation ID: 405272). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. 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	RCV001015470	SCV001176306	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-24	criteria provided, single submitter	clinical testing	The p.R808C variant (also known as c.2422C>T), located in coding exon 11 of the BLM gene, results from a C to T substitution at nucleotide position 2422. The arginine at codon 808 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in 1/847 individuals with early-onset undefined colorectal cancer who previously tested negative for mutations in APC, MLH1, SMAD4, BMPR1A, MUTYH, MSH2, MSH6, PMS2, POLE and POLD1, and this alteration was not detected in 1609 controls (Dobbins SE et al. Fam Cancer, 2016 10;15:593-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV003148741	SCV003837180	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27356891)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003148741	SCV005624251	uncertain significance	not provided	2024-02-13	criteria provided, single submitter	clinical testing	The BLM c.2422C>T (p.Arg808Cys) variant has been reported in the published literature in an individual with early onset colorectal cancer (PMID: 27356891 (2016)). The frequency of this variant in the general population, 0.00007 (9/129154 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000471360	SCV005640457	uncertain significance	Bloom syndrome	2024-04-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000471360	SCV002088067	uncertain significance	Bloom syndrome	2020-02-27	no assertion criteria provided	clinical testing