Submissions for variant NM_000057.4(BLM):c.2619G>C (p.Lys873Asn)

gnomAD frequency: 0.00006  dbSNP: rs146723808

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469889	SCV000543360	uncertain significance	Bloom syndrome	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 873 of the BLM protein (p.Lys873Asn). This variant is present in population databases (rs146723808, gnomAD 0.01%). 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: 405297). 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%. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 23129629). 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	RCV000570597	SCV000672945	likely benign	Hereditary cancer-predisposing syndrome	2020-01-17	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.
Fulgent Genetics, Fulgent Genetics	RCV000469889	SCV000896486	uncertain significance	Bloom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV003105908	SCV003761717	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate DNA damage response comparable to wild type (Mirzaei et al., 2012); This variant is associated with the following publications: (PMID: 23129629)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003105908	SCV005624254	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	The BLM c.2619G>C (p.Lys873Asn) variant has not been reported in individuals with BLM-related conditions in the published literature. Published functional studies show that this variant has been reported to have no significant effect on hypersensitivity to a DNA damaging agent (PMID: 23129629 (2012)). The frequency of this variant in the general population, 0.0001 (13/129076 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.
Natera, Inc.	RCV000469889	SCV001454860	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing