Submissions for variant NM_000057.4(BLM):c.3028del (p.Asp1010fs)

gnomAD frequency: 0.00002  dbSNP: rs780379121

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169440	SCV000220857	likely pathogenic	Bloom syndrome	2014-11-06	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169440	SCV000623297	pathogenic	Bloom syndrome	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp1010Metfs*24) 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 (rs780379121, gnomAD 0.004%). 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: 189048). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000574982	SCV000672986	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The c.3028delG pathogenic mutation, located in coding exon 15 of the BLM gene, results from a deletion of one nucleotide at nucleotide position 3028, causing a translational frameshift with a predicted alternate stop codon (p.D1010Mfs*24). This alteration has been reported in three individuals with Bloom syndrome, one of whom was homozygous for c.3028delG (German J et al. Hum. Mutat. 2007 Aug;28:743-53). This alteration was also identified in a cohort of metastatic prostate cancer patients (Ledet EM et al. Prostate. 2020 02;80:235-237). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169440	SCV001363838	pathogenic	Bloom syndrome	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: BLM c.3028delG (p.Asp1010MetfsX24) 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. The variant allele was found at a frequency of 1.2e-05 in 248358 control chromosomes (gnomAD). c.3028delG has been reported in the literature in a homozygous and compound heterozygote individuals affected with Bloom Syndrome (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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001818407	SCV002010757	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818407	SCV002065822	likely pathogenic	not provided	2021-05-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a single base pair deletion in exon 16, c.3028del. This sequence change results in an amino acid frameshift and creates a premature stop codon 24 amino acids downstream of the change, p.Asp1010Metfs*24. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BLM protein with potentially abnormal function. This sequence change has been previously described in the homozygous and compound heterozygous states in three individuals with Bloom syndrome (PMID: 17407155). This sequence change has been described in four non-Finnish European individuals in the gnomAD population database (rs780379121). Collectively these evidences suggest that, the c.3028del change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Fulgent Genetics, Fulgent Genetics	RCV000169440	SCV002798327	pathogenic	Bloom syndrome	2021-12-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169440	SCV004210839	pathogenic	Bloom syndrome	2024-03-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169440	SCV002090506	pathogenic	Bloom syndrome	2017-03-16	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000169440	SCV004171558	pathogenic	Bloom syndrome	2023-11-24	no assertion criteria provided	clinical testing