Submissions for variant NM_000057.4(BLM):c.2923del (p.Gln975fs)

dbSNP: rs367543014

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115301	SCV000149210	pathogenic	not provided	2021-05-24	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 Not observed at significant frequency in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 17407155)
Eurofins Ntd Llc (ga)	RCV000115301	SCV000336681	pathogenic	not provided	2015-10-26	criteria provided, single submitter	clinical testing
Invitae	RCV000034902	SCV000543387	pathogenic	Bloom syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln975Lysfs*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 (rs752505986, gnomAD 0.009%). 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: 42076). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000571923	SCV000672965	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-15	criteria provided, single submitter	clinical testing	The c.2923delC pathogenic mutation, located in coding exon 14 of the BLM gene, results from a deletion of one nucleotide at nucleotide position 2923, causing a translational frameshift with a predicted alternate stop codon (p.Q975Kfs*24). This alteration has been detected in both a homozygous and compound heterozygous state in several individuals with Bloom syndrome (German J et al. Hum. Mutat., 2007 Aug;28:743-53). 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	RCV000034902	SCV001467881	pathogenic	Bloom syndrome	2020-12-11	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2923delC (p.Gln975LysfsX24) 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 2.8e-05 in 251432 control chromosomes. c.2923delC has been reported in the literature in multiple individuals affected with Bloom Syndrome in the homozygous and compound heterozygous state (German_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000115301	SCV002010761	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034902	SCV004210882	pathogenic	Bloom syndrome	2023-06-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914913	SCV004744858	pathogenic	BLM-related condition	2023-10-23	criteria provided, single submitter	clinical testing	The BLM c.2923delC variant is predicted to result in a frameshift and premature protein termination (p.Gln975Lysfs*24). This variant was reported in an individual with Bloom syndrome (German et al 2007. PubMed ID: 17407155). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91333976-AC-A) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42076/). Frameshift variants in BLM are expected to be pathogenic. This variant is interpreted as pathogenic.
Counsyl	RCV000034902	SCV000486234	pathogenic	Bloom syndrome	2016-04-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000034902	SCV002088133	pathogenic	Bloom syndrome	2017-03-17	no assertion criteria provided	clinical testing