Submissions for variant NM_000057.4(BLM):c.2271C>G (p.Asp757Glu)

gnomAD frequency: 0.00001  dbSNP: rs773761682

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001015007	SCV001175790	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The p.D757E variant (also known as c.2271C>G), located in coding exon 9 of the BLM gene, results from a C to G substitution at nucleotide position 2271. The aspartic acid at codon 757 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001120518	SCV001279003	uncertain significance	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, 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.
Invitae	RCV001120518	SCV001412425	uncertain significance	Bloom syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 757 of the BLM protein (p.Asp757Glu). This variant is present in population databases (rs773761682, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 820996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001759694	SCV001996321	uncertain significance	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001015007	SCV002529314	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001120518	SCV002775920	uncertain significance	Bloom syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001120518	SCV002088055	uncertain significance	Bloom syndrome	2020-07-17	no assertion criteria provided	clinical testing