Submissions for variant NM_000057.4(BLM):c.1490A>C (p.Gln497Pro)

dbSNP: rs368547042

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550747	SCV000623241	uncertain significance	Bloom syndrome	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 497 of the BLM protein (p.Gln497Pro). This variant is present in population databases (rs368547042, gnomAD 0.1%). 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: 454080). 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.
Fulgent Genetics, Fulgent Genetics	RCV000550747	SCV000896482	uncertain significance	Bloom syndrome	2021-12-08	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000550747	SCV000898547	uncertain significance	Bloom syndrome	2021-11-23	criteria provided, single submitter	clinical testing	BLM:NM_000057:exon7, p.Gln497Pro (c.1490A>C): This variant has not been reported in the literature but is present in 37/33556 Latino chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs368547042). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Of note, 4 species also carry this variant (Tenrec, Opossum, Tasmanian devil, Wallaby), further suggesting that this variant may not be damaging. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV001011867	SCV001172242	likely benign	Hereditary cancer-predisposing syndrome	2023-04-11	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.
Genome-Nilou Lab	RCV000550747	SCV001781340	uncertain significance	Bloom syndrome	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001788276	SCV002030918	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001788276	SCV004222431	uncertain significance	not provided	2024-10-20	criteria provided, single submitter	clinical testing	The BLM c.1490A>C (p.Gln497Pro) variant has not been reported as a germline variant in individuals with BLM-related conditions in the published literature. The frequency of this variant in the general population, 0.0011 (38/34564 chromosomes in Admixed American subpopulation (Genome Aggregation Database, 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000550747	SCV005689312	uncertain significance	Bloom syndrome	2024-08-03	criteria provided, single submitter	clinical testing	The BLM c.1490A>C; p.Gln497Pro missense variant has a maximum subpopulation frequency of 0.11% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with Bloom syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000550747	SCV005876478	uncertain significance	Bloom syndrome	2023-12-07	criteria provided, single submitter	clinical testing