Submissions for variant NM_000057.4(BLM):c.3041A>G (p.His1014Arg)

gnomAD frequency: 0.00032  dbSNP: rs145022945

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228961	SCV000283130	benign	Bloom syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563912	SCV000672898	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	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.
GeneKor MSA	RCV000563912	SCV000821794	likely benign	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000228961	SCV000838980	uncertain significance	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000228961	SCV001273605	uncertain significance	Bloom syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001538791	SCV001756489	uncertain significance	not provided	2019-10-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign in association with a neurodevelopmental phenotype to our knowledge; This variant is associated with the following publications: (PMID: 23129629, 31159747, 28805986)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804962	SCV002051095	likely benign	not specified	2021-12-14	criteria provided, single submitter	clinical testing	Variant summary: BLM c.3041A>G (p.His1014Arg) results in a non-conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) 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 0.00043 in 280338 control chromosomes, predominantly at a frequency of 0.0097 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BLM causing Bloom Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.3041A>G has been reported in the literature in one individual who had genetic testing with a hereditary cancer panel (Tsaousis_2019). The report does not provide unequivocal conclusions about association of the variant with Bloom Syndrome. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Mirzaei_2012). Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001804962	SCV002071129	likely benign	not specified	2018-06-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563912	SCV002530027	likely benign	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001538791	SCV004222471	benign	not provided	2022-12-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000228961	SCV001461113	likely benign	Bloom syndrome	2019-08-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907844	SCV004719547	likely benign	BLM-related disorder	2019-03-20	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).