Submissions for variant NM_000057.4(BLM):c.887A>G (p.Tyr296Cys)

dbSNP: rs775005766

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460689	SCV000543370	uncertain significance	Bloom syndrome	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 296 of the BLM protein (p.Tyr296Cys). This variant is present in population databases (rs775005766, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 405307). 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 not expected to disrupt BLM protein function with a negative 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	RCV001018434	SCV001179672	likely benign	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV001821232	SCV002065280	uncertain significance	not specified	2021-05-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.887A>G, in exon 4 that results in an amino acid change, p.Tyr296Cys. This sequence change has been described in gnomAD with a frequency of 0.069% in the South Asian sub-population (dbSNP rs775005766). The p.Tyr296Cys change affects a poorly conserved amino acid residue located in a domain of the BLM protein that is not known to be functional. The p.Tyr296Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with BLM-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Tyr296Cys change remains unknown at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477941	SCV004222511	uncertain significance	not provided	2022-10-27	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00069 (21/30608 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.