Submissions for variant NM_000057.4(BLM):c.43C>T (p.Arg15Cys)

gnomAD frequency: 0.00029  dbSNP: rs148545569

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227410	SCV000283150	likely benign	Bloom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572998	SCV000672914	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Mendelics	RCV000227410	SCV000838940	uncertain significance	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000857675	SCV002028577	uncertain significance	not provided	2021-11-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in the germline to our knowledge; This variant is associated with the following publications: (PMID: 31956452)
Sema4, Sema4	RCV000572998	SCV002533096	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-13	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226261	SCV003923073	uncertain significance	not specified	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: BLM c.43C>T (p.Arg15Cys) results in a non-conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 247840 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.00024 vs 0.0035), allowing no conclusion about variant significance. c.43C>T has been reported in the literature in heterozygous individuals affected with BLM1-related conditions, including pediatric cancer, immune deficiency, and malignant mesothelioma, however without strong evidence for causality (e.g., Gururangan_2015, Zhang_2015, Rudilla_2019, Viallard_2019, Bononi_2020). These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and have reported the variant with conflicting assessments, classifying the variant as uncertain significance (n = 3) or likely benign (n = 3). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003407767	SCV004113244	uncertain significance	BLM-related condition	2023-05-19	criteria provided, single submitter	clinical testing	The BLM c.43C>T variant is predicted to result in the amino acid substitution p.Arg15Cys. This variant has been reported in individuals with peritoneal malignant mesothelioma (Bononi et al. 2020. PubMed ID: 33318203) and pediatric onset melanoma (Table S4b - Zhang et al. 2015. PubMed ID: 26580448). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91290665-C-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/236821/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000857675	SCV004222500	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0011 (12/11356 chromosomes in Southern European subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with peritoneal malignant mesothelioma and a rare case of immune thrombocytopenia (ITP) (PMID: 33318203 (2020), 31956452 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV000227410	SCV002089880	likely benign	Bloom syndrome	2021-05-25	no assertion criteria provided	clinical testing