Submissions for variant NM_000057.4(BLM):c.1624del (p.Asp542fs)

dbSNP: rs747498968

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012466	SCV001172922	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	The c.1624delG pathogenic mutation, located in coding exon 6 of the BLM gene, results from a deletion of one nucleotide at nucleotide position 1624, causing a translational frameshift with a predicted alternate stop codon (p.D542Tfs*2). This mutation has been detected in conjunction with a pathogenic nonsense mutation in an individual with Bloom Syndrome (Adams M et al. J Genet Syndr Gene Ther, 2013 Sep;4). Additionally, this alteration was detected in a heterozygous state in 1/2000 individuals with breast cancer and 0/1997 controls from Australia (Thompson ER et al. J. Clin. Oncol. 2016 May;34(13):1455-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389843	SCV001591359	pathogenic	Bloom syndrome	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp542Thrfs*2) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant is present in population databases (rs747498968, gnomAD 0.0009%). 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: 819694). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001389843	SCV002018484	pathogenic	Bloom syndrome	2019-05-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001389843	SCV004210848	pathogenic	Bloom syndrome	2023-10-05	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001389843	SCV005086350	pathogenic	Bloom syndrome	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bloom syndrome (MIM#210900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by several clinical laboratories in ClinVar and observed as compound heterozygous in an individual with Bloom syndrome (PMIDs: 24932421). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV004726779	SCV005338810	pathogenic	BLM-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The BLM c.1624delG variant is predicted to result in a frameshift and premature protein termination (p.Asp542Thrfs*2). This variant has been reported as compound heterozygous with a nonsense variant in BLM in an individual with Bloom syndrome (Adams et al 2013. PubMed ID: 24932421) and as heterozygous in an individual with breast cancer from a cohort study of breast cancer patients (Thompson et al 2016. PubMed ID: 26786923). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/819694/). Frameshift variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic.