Submissions for variant NM_000057.4(BLM):c.205G>A (p.Glu69Lys)

dbSNP: rs746195311

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673383	SCV000798580	uncertain significance	Bloom syndrome	2018-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673383	SCV000820385	uncertain significance	Bloom syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 69 of the BLM protein (p.Glu69Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with aplastic anemias (PMID: 27124789). ClinVar contains an entry for this variant (Variation ID: 191064). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000673383	SCV000845548	uncertain significance	Bloom syndrome	2018-08-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000673383	SCV001139689	uncertain significance	Bloom syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014270	SCV001174961	likely benign	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Sema4, Sema4	RCV001014270	SCV002533702	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298500	SCV002598910	uncertain significance	not specified	2022-09-28	criteria provided, single submitter	clinical testing	Variant summary: BLM c.205G>A (p.Glu69Lys) results in a conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251086 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in BLM causing Bloom Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. To our knowledge c.205G>A has not been reported in the literature in individuals affected with Bloom Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000673383	SCV002783419	uncertain significance	Bloom syndrome	2022-03-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000673383	SCV005044833	uncertain significance	Bloom syndrome		criteria provided, single submitter	clinical testing	The missense c.205G>A p.Glu69Lys variant in BLM gene has been reported in multiple individuals affected with aplastic anemias Abouelhoda et al., 2016. The variant is reported with allele frequency of 0.01% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Variant of Uncertain Significance multiple submissions. The amino acid change p.Glu69Lys in BLM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 69 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000171242	SCV000221439	likely pathogenic	not provided		flagged submission	research