BLM

Inheritance Pattern: AD

Disease ID:MONDO:0005575

Submitter: ClinGen

​​The BLM gene (BLM RecQ Like Helicase) was first reported in relation to autosomal dominant hereditary colorectal cancer (CRC) predisposition in 2002 (Goss et al., PMID: 12242442). Variants in BLM have been reported in individuals with the following disease entities: Bloom syndrome (MONDO:0008876) and CRC predisposition (MONDO:0005575).Based on the criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in inheritance pattern and phenotypic variability between Bloom syndrome and CRC predisposition. Therefore, the following disease entities have been split into multiple disease entities, Bloom syndrome (MONDO:0008876) and CRC predisposition (MONDO:0005575). Bloom syndrome has been assessed separately, and this curation addresses CRC predisposition. Documented here is the curation for individuals with heterozygous loss of function variants under colorectal cancer. However, the genetic and experimental evidence supporting this gene-disease relationship is limited. Additionally, the literature was reviewed for potential associations between autosomal dominant BLM and other cancer types, including breast and ovarian cancers (PMIDs: 32566746, 23225144, 25182961, 25399228, 23028338) and prostate cancer (PMIDs: 29439820, 24096176, 31816118, 25472581). However, there is insufficient evidence to establish a significant relationship between BLM and these cancer types. Case control data: This gene-disease relationship with colorectal cancer has been studied in at least two case-control studies (PMID:12242432, PMID:26358404) at the single variant level. PMID:12242432 performed a case-control study and concluded that Ashkenazi Jews with CRC were more than twice as likely to carry BLM variants compared to Ashkenazi Jewish controls without CRC. However, this finding lacks broader population data and is limited to participants of Ashkenazi Jewish descent. In 2015, de Voer et al., provided further support for the BLM gene-disease relationship by showing that young adults with CRC were significantly more likely to have heterozygous BLM loss of function variants than controls. They identified five pathogenic/likely pathogenic variants in young CRC patients. However, studies by PMIDs: 30871259, 29478780, and 27356891) did not replicate these findings, thereby limiting the robustness of the genetic evidence (PMID:30871259, PMID:29478780, PMID:27356891). Experimental Evidence: PMID: 11101838 found that 29% of mice with homozygous BLM alleles developed cancer by 20 months, unlike wild-type mice. The observed cancers included sarcomas, lymphomas, and carcinomas (PMID:11101838 ). However, as the study focused on homozygous Blm-deficient mice, its relevance to the autosomal dominant inheritance of BLM in CRC is limited and was downscored. PMID: 12242442 demonstrated an interaction between BLM and APC, showing that BLM heterozygosity increased adenoma formation in the presence of an APC mutation (PMID:12242442). However, the study did not directly assess the impact of BLM heterozygosity alone on tumor formation in CRC and was downscored as well. PMID:14642567 highlighted that mice with mutations in both BLM alleles, particularly different mutations in each allele, were more prone to tumor formation(PMID:14642567). This underscores the importance of BLM in maintaining genomic stability and preventing cancer although again better reflects the recessive disorder. PMID: 29386092 demonstrated that miR-522-3p upregulation negatively regulates the expression of BLM, with upregulation of c-myc, CDK2, and cyclin E, and thereby promoting the proliferation of human CRC cells (PMID:29386092). PMID: 15064730 found that hMSH2/6 formed a complex with BLM–p53–RAD51 in response to the damaged DNA forks during double-stranded break repair. However, these experimental studies do not establish a direct association between BLM and hereditary CRC with two studies (PMIDs:15064730 & 29386092) scored with the default points and the remaining studies being downscored from the default point value. Current genetic and experimental evidence does not provide significant support for a strong association between the BLM gene and hereditary colorectal cancer (CRC). While certain studies suggest potential links, the evidence is limited and inconsistent, with significant gaps in understanding the direct role of BLM in hereditary CRC. Therefore, the association between BLM and hereditary CRC remains limited. This classification was approved by the ClinGen Hereditary Cancer GCEP on the meeting date November 22, 2024 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: ClinGen

There has been substantial evidence published associating the BLM gene with Bloom syndrome since the gene-disease relationship was first proposed by Ellis et al. (1995). Multiple case level studies have been performed with BS patients that have variants in the BLM gene. WRN and RECQL4, another two RecQ DNA helicases, are associated with Werner and Rothmund–Thomson syndromes. All three are disorders of chromosomal instability and manifest growth retardation, and predisposition to malignancies. Northern blot analysis of mRNAs derived from selected Bloom’s syndrome cell lines showed absent or abnormal BLM RNA. Multiple BLM deficient mouse models have been established to show consistent phenotypes with BS patients, especially increased rate of SCE and the development of a wide spectrum of cancer. All of these types of evidence combined are consistent with a definitive relationship between the BLM gene and Bloom Syndrome (BS).

Inheritance Pattern: AR

Disease ID:MONDO:0009807

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018630

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0023113

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: Myriad Women's Health

Inheritance Pattern: AR

Disease ID:MONDO:0008876

Submitter: PanelApp Australia