Submissions for variant NM_000057.4(BLM):c.3505G>A (p.Ala1169Thr)

gnomAD frequency: 0.00001  dbSNP: rs777492549

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628682	SCV000749588	uncertain significance	Bloom syndrome	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1169 of the BLM protein (p.Ala1169Thr). This variant is present in population databases (rs777492549, gnomAD 0.04%). 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: 524814). 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. 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	RCV001020473	SCV001181959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The p.A1169T variant (also known as c.3505G>A), located in coding exon 17 of the BLM gene, results from a G to A substitution at nucleotide position 3505. The alanine at codon 1169 is replaced by threonine, an amino acid with similar properties. This alteration was identified in 1/1358 non-cancer control individuals and was not observed in 57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098).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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800832	SCV002047041	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000628682	SCV002786032	uncertain significance	Bloom syndrome	2021-09-09	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153769	SCV003843528	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000628682	SCV002090577	uncertain significance	Bloom syndrome	2018-10-29	no assertion criteria provided	clinical testing