Submissions for variant NM_000057.4(BLM):c.2263A>G (p.Lys755Glu)

gnomAD frequency: 0.00140  dbSNP: rs142551229

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469034	SCV000555826	benign	Bloom syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120225	SCV000593644	likely benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566842	SCV000672870	likely benign	Hereditary cancer-predisposing syndrome	2019-03-22	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.
Mendelics	RCV003492521	SCV000838968	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731068	SCV000858839	uncertain significance	not provided	2017-12-26	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000731068	SCV002010765	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000731068	SCV002032583	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: showed similar effects on hypersensitivity to the DNA-damaging agent hypdroxyuruea as the wild type (Mirzaei 2012); Identified in healthy individuals undergoing whole genome sequencing (Bodian 2014); This variant is associated with the following publications: (PMID: 24728327, 23129629)
Sema4, Sema4	RCV000566842	SCV002529292	likely benign	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120225	SCV002598922	likely benign	not specified	2022-09-19	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2263A>G (p.Lys755Glu) results in a conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251136 control chromosomes (gnomAD and Bodian_2014), predominantly at a frequency of 0.0042 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), suggesting that the variant may be a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2263A>G in individuals affected with Bloom Syndrome has been reported. At least one publication reported experimental evidence evaluating an impact of the variant on protein function in a humanized yeast model system treated with a DNA damaging agent (e.g. Mirzaei_2012). The results showed no difference in sensitivity compared to WT, suggesting the variant does not have a damaging effect on the ability of the protein to maintain genome stability. Nine submitters have provided assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS n=4, likely benign n=4, benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000731068	SCV004222448	benign	not provided	2023-02-04	criteria provided, single submitter	clinical testing
ITMI	RCV000120225	SCV000084371	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000469034	SCV001461838	likely benign	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905143	SCV004720162	likely benign	BLM-related disorder	2022-04-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).