Submissions for variant NM_000057.4(BLM):c.772_773del (p.Leu258fs)

dbSNP: rs367543013

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000034918	SCV000220377	likely pathogenic	Bloom syndrome	2014-06-04	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034918	SCV000694481	pathogenic	Bloom syndrome	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The BLM c.772_773delCT (p.Leu258Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BLM 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 (e.g. c.2207_2212delinsTAGATTC (p.Tyr736fs) and c.1642C>T (p.Gln548X)). One in silico tool predicts a damaging outcome for this variant. This variant was found in 5/119222 control chromosomes at a frequency of 0.0000419, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). The variant has been reported in at least one homozygous affected individual in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as "pathogenic."
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034918	SCV000749564	pathogenic	Bloom syndrome	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu258Glufs*7) 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 (rs760209332, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome and breast and ovarian cancer (PMID: 17407155, 24448499, 28724667). This variant is also known as c.768_769del, p.D256fs. ClinVar contains an entry for this variant (Variation ID: 42092). For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV000034918	SCV002098975	pathogenic	Bloom syndrome	2021-03-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399367	SCV002669910	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The c.772_773delCT pathogenic mutation, located in coding exon 2 of the BLM gene, results from a deletion of two nucleotides at nucleotide positions 772 to 773, causing a translational frameshift with a predicted alternate stop codon (p.L258Efs*7). This mutation has been reported in the homozygous and compound heterozygous states in patients with Bloom syndrome (German J et al. Hum Mutat, 2007 Aug;28:743-53; Wu ML et al. Zhonghua Er Ke Za Zhi, 2018 May;56:373-376). This mutation has also been reported in a patient with ovarian cancer (Kanchi KL et al. Nat Commun, 2014;5:3156). 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.
GeneDx	RCV003162295	SCV003915236	pathogenic	not provided	2022-10-07	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; Identified in the heterozygous state in individuals with breast, ovarian, or colorectal cancer (Kanchi et al., 2014; Sun et al., 2017; Huang et al., 2018); This variant is associated with the following publications: (PMID: 26247052, 17407155, 24448499, 28724667, 29625052, 29783825, 29478780, 31721094)
Baylor Genetics	RCV000034918	SCV004210854	pathogenic	Bloom syndrome	2024-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003162295	SCV004222505	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	This variant alters the translational reading frame of the BLM mRNA and causes the premature termination of BLM protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 36315097 (2022), 28724667 (2017)), rectal cancer (PMID: 29625052 (2018)), colorectal cancer (PMID: 29478780 (2018)), lung cancer (PMID: 35273153 (2022), 31721094 (2020)), and astrocytoma (PMID: 32783018 (2019), 31133068 (2019)). This variant has also been observed in individuals with Bloom Syndrome (PMID: 29783825 (2018), 17407155 (2007)). The frequency of this variant in the general population, 0.00016 (4/24446 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000034918	SCV005418527	pathogenic	Bloom syndrome		criteria provided, single submitter	clinical testing	PVS1+PM2_Supporting+PM3_Strong+PP1+PP4
Natera, Inc.	RCV000034918	SCV002089970	pathogenic	Bloom syndrome	2017-03-17	no assertion criteria provided	clinical testing