Submissions for variant NM_000057.4(BLM):c.2371C>T (p.Arg791Cys)

gnomAD frequency: 0.00004  dbSNP: rs55880859

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568596	SCV000672919	likely benign	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000628631	SCV000749535	uncertain significance	Bloom syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 791 of the BLM protein (p.Arg791Cys). This variant is present in population databases (rs55880859, gnomAD 0.1%). 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: 133698). 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. Experimental studies have shown that this missense change affects BLM function (PMID: 23129629, 24816114, 26788541). 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.
Counsyl	RCV000628631	SCV000790160	uncertain significance	Bloom syndrome	2017-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000628631	SCV000896483	uncertain significance	Bloom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120226	SCV000918647	uncertain significance	not specified	2018-02-23	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2371C>T (p.Arg791Cys) results in a non-conservative amino acid change located in the Helicase superfamily 1/2, ATP-binding domain and DEAD/DEAH box helicase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277226 control chromosomes. This frequency is not higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. The c.2371C>T variant has been reported in the literature in a cancer cell line from a Bloom Syndrome patient. This report does not provide strong evidence about an association of the variant with Bloom Syndrome. Several publications report experimental evidence evaluating an impact on protein function. In one study (Shastri_2015), the variant showed no significant sensitivity to hydroxyurea. However, it showed delayed accumulation and elimination of phosphorylated H2AX upon DNA damage. Moreover, the variant showed a significantly increased level of sister chromatid exchanges compared WT controls. Another study (Mirzaei_2012) described the variant as a partial loss of function via yeast growth assays, and suggested this was due to the variants proximity to an invariant residue (D795), thus causing only a partial loss of ATP hydrolysis activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030455	SCV001193515	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Pars Genome Lab	RCV000628631	SCV001736766	uncertain significance	Bloom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568596	SCV002529381	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
ITMI	RCV000120226	SCV000084372	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000628631	SCV001454854	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing