Submissions for variant NM_000057.4(BLM):c.2867C>T (p.Pro956Leu)

gnomAD frequency: 0.00001  dbSNP: rs962069708

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693179	SCV000821036	uncertain significance	Bloom syndrome	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 956 of the BLM protein (p.Pro956Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 571919). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BLM protein function with a positive 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.
GeneKor MSA	RCV000708666	SCV000821901	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708666	SCV004076439	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The p.P956L variant (also known as c.2867C>T), located in coding exon 14 of the BLM gene, results from a C to T substitution at nucleotide position 2867. The proline at codon 956 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478419	SCV004222466	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	This variant has been reported in the published literature in an individual with personal or family history of breast/ovarian cancer (PMID: 31159747 (2019)). In our internal patient population, this variant co-occurred with a pathogenic variant in the BRCA2 gene in an individual affected with breast cancer, suggesting this variant was not the primary cause of disease. The frequency of this variant in the general population, 0.000008 (2/251432 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056438	SCV005726970	uncertain significance	not specified	2024-11-07	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2867C>T (p.Pro956Leu) results in a non-conservative amino acid change located in the P-loop containing nucleotide triphosphate hydrolases domain (IPR027417) 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 8e-06 in 251432 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2867C>T has been reported in the literature in one individual affected with hereditary cancer predisposition syndrome (Tsaousis_2019). The report does 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. The following publications have been ascertained in the context of this evaluation (PMID: 31159747, 34966786). ClinVar contains an entry for this variant (Variation ID: 571919). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000693179	SCV002088127	uncertain significance	Bloom syndrome	2019-02-14	no assertion criteria provided	clinical testing