Submissions for variant NM_000057.4(BLM):c.3427G>A (p.Glu1143Lys)

gnomAD frequency: 0.00008  dbSNP: rs140387675

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115307	SCV000149216	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate: sensitivity to hydroxyurea similar to wildtype, suggesting no significant impact on helicase activity (PMID: 23129629); Observed in individuals with a personal or family history including colorectal and breast and/or ovarian cancer (PMID: 30262796, 31159747, 32449991, 35264596, 35957908); This variant is associated with the following publications: (PMID: 32449991, 30262796, 31159747, 27516001, 33528079, 23129629, 35264596, 28944238, 35957908)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475273	SCV000543395	uncertain significance	Bloom syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1143 of the BLM protein (p.Glu1143Lys). This variant is present in population databases (rs140387675, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of BLM-related conditions (PMID: 30262796, 35957908). ClinVar contains an entry for this variant (Variation ID: 127499). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect BLM function (PMID: 23129629). 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.
Ambry Genetics	RCV000566047	SCV000672921	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	The p.E1143K variant (also known as c.3427G>A), located in coding exon 17 of the BLM gene, results from a G to A substitution at nucleotide position 3427. The glutamic acid at codon 1143 is replaced by lysine, an amino acid with similar properties. This alteration did not show hypersensitivity to the DNA damaging agent hydroxyurea, as compared to the wild-type allele, in a humanized yeast model (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A. 2012 Nov;109:19357-62). This alteration has been reported in an individual with a personal history of five primary malignant cancers and a family history consistent with Li Fraumeni syndrome, who was identified to carry TP53 p.R175H (Zampiga V et al. Int J Biol Markers, 2016 Dec;31:e461-e465). This variant has also been reported in multiple cohorts undergoing evaluation for inherited cancer predisposition (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneKor MSA	RCV000566047	SCV000821904	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000475273	SCV000838984	uncertain significance	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000115307	SCV001149592	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000475273	SCV001781337	uncertain significance	Bloom syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818265	SCV002071142	uncertain significance	not specified	2021-05-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.3427G>A, in exon 18 that results in an amino acid change, p.Glu1143Lys. This sequence change has been described in gnomAD with a frequency of 0.02% in the East Asian sub-population (dbSNP rs140387675). The p.Glu1143Lys change affects a moderately conserved amino acid residue located in a domain of the BLM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu1143Lys substitution. This sequence change does not appear to have been previously described in patients with BLM-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Glu1143Lys change remains unknown at this time.
Revvity Omics, Revvity	RCV000475273	SCV003831473	uncertain significance	Bloom syndrome	2019-11-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115307	SCV004222481	likely benign	not provided	2023-02-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000115307	SCV005194011	uncertain significance	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818265	SCV005395169	uncertain significance	not specified	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: BLM c.3427G>A (p.Glu1143Lys) results in a conservative amino acid change located in the RQC domain (IPR018982) 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 0.00011 in 251310 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BLM causing Bloom Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.3427G>A has been reported in the literature in the heterozygous state in individuals affected with colorectal cancer, breast and/or ovarian cancer, pancreatic cancer, and epilepsy (e.g. Tian_2021, Gifoni_2022, Quezada Urban_2018, Guindalini_2022, Atli_2022, Emelyanova_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Mirzaei_2012). The following publications have been ascertained in the context of this evaluation (PMID: 33528079, 35309086, 35957908, 35264596, 23129629, 30262796, 34512202). ClinVar contains an entry for this variant (Variation ID: 127499). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000475273	SCV002090568	uncertain significance	Bloom syndrome	2018-06-20	no assertion criteria provided	clinical testing