Submissions for variant NM_000057.4(BLM):c.2268A>G (p.Lys756=)

gnomAD frequency: 0.00163  dbSNP: rs146013879

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000123846	SCV000167189	benign	not specified	2013-10-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226761	SCV000283121	benign	Bloom syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000123846	SCV000339654	likely benign	not specified	2016-02-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000226761	SCV000394418	uncertain significance	Bloom syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV000565012	SCV000672878	likely benign	Hereditary cancer-predisposing syndrome	2016-09-30	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.
Genome-Nilou Lab	RCV000226761	SCV001737241	likely benign	Bloom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123846	SCV002069603	likely benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565012	SCV002529303	likely benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001705903	SCV002545314	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BLM: BP4, BP7
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001705903	SCV004222449	benign	not provided	2022-10-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123846	SCV005203955	benign	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2268A>G alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 1599836 control chromosomes, predominantly at a frequency of 0.004 within the South Asian subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035). c.2268A>G has been reported in the literature in at least an individual from families with an accumulation of colorectal cancers or with only one sporadic case of very early onset colorectal cancer (example: Djursby_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 33193653). ClinVar contains an entry for this variant (Variation ID: 136514). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705903	SCV001929021	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705903	SCV001976056	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000226761	SCV002088054	likely benign	Bloom syndrome	2017-05-15	no assertion criteria provided	clinical testing