Submissions for variant NM_000057.4(BLM):c.842A>C (p.His281Pro)

gnomAD frequency: 0.00014  dbSNP: rs202042636

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656780	SCV000149234	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465275	SCV000543345	uncertain significance	Bloom syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 281 of the BLM protein (p.His281Pro). This variant is present in population databases (rs202042636, gnomAD 0.02%). 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: 127517). 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	RCV000561026	SCV000672889	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-29	criteria provided, single submitter	clinical testing	The p.H281P variant (also known as c.842A>C), located in coding exon 3 of the BLM gene, results from an A to C substitution at nucleotide position 842. The histidine at codon 281 is replaced by proline, an amino acid with similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE, 2014 Apr;9:e94554). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000465275	SCV000896479	uncertain significance	Bloom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120242	SCV004020834	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: BLM c.842A>C (p.His281Pro) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251246 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.0001 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, c.842A>C has not been reported in the literature in individuals affected with Bloom Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24728327). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003390798	SCV004121119	uncertain significance	BLM-related disorder	2022-11-11	criteria provided, single submitter	clinical testing	The BLM c.842A>C variant is predicted to result in the amino acid substitution p.His281Pro. To variant has been documented in a healthy and ancestrally diverse cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91295059-A-C) and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127517). 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	RCV000656780	SCV004222509	uncertain significance	not provided	2024-04-19	criteria provided, single submitter	clinical testing	The BLM c.842A>C (p.His281Pro) variant has been reported in the published literature in families at high risk for breast and ovarian cancer (PMIDs: 27153395 (2016) and 30306255 (2018)) as well as in a reportedly healthy individual (PMID: 24728327 (2014)). The frequency of this variant in the general population, 0.0002 (7/35430 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000465275	SCV005878217	uncertain significance	Bloom syndrome	2024-07-17	criteria provided, single submitter	clinical testing
ITMI	RCV000120242	SCV000084390	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000465275	SCV001460762	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing