Submissions for variant NM_000057.4(BLM):c.2506_2507del (p.Arg836fs)

gnomAD frequency: 0.00001  dbSNP: rs367543024

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000034897	SCV000486883	pathogenic	Bloom syndrome	2016-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574956	SCV000672963	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	The c.2506_2507delAG pathogenic mutation, located in coding exon 11 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 2506 to 2507, causing a translational frameshift with a predicted alternate stop codon (p.R836Gfs*18). This mutation has been reported in the homozygous and compound heterozygous state in patients with Bloom syndrome (German J et al. Hum. Mutat., 2007 Aug;28:743-53). This alteration has also been reported in one individual with cervical squamous cell carcinoma and another individual with liposarcoma (Huang KL et al. Cell, 2018 04;173:355-370.e14). 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.
Invitae	RCV000034897	SCV000749524	pathogenic	Bloom syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg836Glyfs*18) 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 (rs367543024, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42071). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034897	SCV001338365	pathogenic	Bloom syndrome	2021-03-05	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2506_2507delAG (p.Arg836GlyfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 7.6e-05 in 251380 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (7.6e-05 vs 0.0035), allowing no conclusion about variant significance. c.2506_2507delAG has been reported in the literature in homozygous and compound heterozygous individuals affected with Bloom Syndrome (e.g. German_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001731330	SCV001983841	pathogenic	not provided	2022-06-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29625052, 33832920, 17407155, 26247052)
Sema4, Sema4	RCV000574956	SCV002529392	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
Baylor Genetics	RCV000034897	SCV004040969	pathogenic	Bloom syndrome	2023-01-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001731330	SCV004222453	pathogenic	not provided	2022-10-11	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BLM mRNA and causes the premature termination of BLM protein synthesis. In the published literature, the variant has been reported in individuals affected with advanced cancers (PMID: 29625052 (2018)) and Bloom syndrome with a second pathogenic variant (PMID: 17407155 (2007)). One family study showed the variant segregated with disease (PMID: 33832920 (2021)). Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003944888	SCV004762814	pathogenic	BLM-related condition	2023-12-29	criteria provided, single submitter	clinical testing	The BLM c.2506_2507delAG variant is predicted to result in a frameshift and premature protein termination (p.Arg836Glyfs*18). This variant was reported in the homozygous or compound heterozygous state in individuals with Bloom syndrome (German et al. 2007. PubMed ID: 17407155; Sybouts et al. 2021. PubMed ID: 33832920). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic.
Greehey Children's Cancer Research Institute, UT Health San Antonio	RCV000034897	SCV001481971	pathogenic	Bloom syndrome	2020-08-01	no assertion criteria provided	clinical testing	The proband, a Hispanic male child from the US-Mexico border, had features of Bloom syndrome including short stature, failure to thrive, microcephaly, a long thin face with coarse facial features, little subcutaneous fat, and multi-pigmented skin lesions. At age 3 the proband developed rhabdomyosarcoma, a tumor type not previously observed in Bloom syndrome. He was found to be homozygous for BLM c.2506_2507delAG variant, a variant previously described in two other individuals, one Mexican and one from New Mexico. Using flanking markers a common homozygous haplotype was revealed in our patient as well as his two affected siblings, suggesting that this variant is a previously unrecognized founder mutation in the Mexican population.
Natera, Inc.	RCV000034897	SCV002088077	pathogenic	Bloom syndrome	2017-03-16	no assertion criteria provided	clinical testing