Submissions for variant NM_000057.4(BLM):c.1097T>C (p.Ile366Thr)

gnomAD frequency: 0.00011  dbSNP: rs571152089

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115278	SCV000149187	uncertain significance	not provided	2024-08-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26979391)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477302	SCV000543398	uncertain significance	Bloom syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 366 of the BLM protein (p.Ile366Thr). This variant is present in population databases (rs571152089, gnomAD 0.03%). 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: 127472). 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	RCV000574582	SCV000672897	likely benign	Hereditary cancer-predisposing syndrome	2023-06-28	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.
Baylor Genetics	RCV000477302	SCV002030115	uncertain significance	Bloom syndrome	2021-05-31	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000574582	SCV002531260	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115278	SCV004222424	uncertain significance	not provided	2024-09-29	criteria provided, single submitter	clinical testing	The BLM c.1097T>C (p.Ile366Thr) variant has been reported in the published literature as a somatic mutation in a sample with primary myelofibrosis (PMID: 26979391 (2016)). The frequency of this variant in the general population, 0.00054 (19/35410 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.