Submissions for variant NM_000057.4(BLM):c.11T>C (p.Val4Ala)

gnomAD frequency: 0.00102  dbSNP: rs144706057

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656774	SCV000149188	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747, 23028338, 19917125, 30666157)
CSER _CC_NCGL, University of Washington	RCV000210906	SCV000264592	uncertain significance	Bloom syndrome	2016-01-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000210906	SCV000283111	benign	Bloom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210906	SCV000394406	likely benign	Bloom syndrome	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV000115279	SCV000593630	uncertain significance	not specified	2017-05-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000210906	SCV000611374	uncertain significance	Bloom syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562058	SCV000672883	likely benign	Hereditary cancer-predisposing syndrome	2020-10-27	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.
Eurofins Ntd Llc (ga)	RCV000656774	SCV000704456	uncertain significance	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000210906	SCV000809075	uncertain significance	Bloom syndrome	2016-08-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000562058	SCV000821898	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492469	SCV000838938	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000115279	SCV000918648	uncertain significance	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: BLM c.11T>C (p.Val4Ala) results in a non-conservative amino acid change located in the Bloom syndrome protein, N-terminal domain 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 0.0011 in 245310 control chromosomes. This frequency is not significantly higher than the estimated maximum frequency expected for a pathogenic variant in BLM causing Bloom Syndrome (0.0011 vs 0.0035), allowing no conclusion about variant significance. c.11T>C has been reported in the literature in individuals affected with Prostate cancer and Non-Hodkin Lymphoma (NHL), and in Hereditary Breast and Ovarian Cancer (HBOC) families (e.g. Hunter_2016, Schuetz_2009, Thompson_2012, Bonache_2018, Tsaousis_2019). These reports 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=12; benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000656774	SCV001334805	uncertain significance	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000210906	SCV001482834	uncertain significance	Bloom syndrome	2020-05-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656774	SCV002010769	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562058	SCV002531271	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	curation
Natera, Inc.	RCV000210906	SCV001456974	uncertain significance	Bloom syndrome	2017-05-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935097	SCV004747997	likely benign	BLM-related disorder	2022-05-13	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).