Submissions for variant NM_000057.4(BLM):c.2720C>T (p.Thr907Met)

gnomAD frequency: 0.00007  dbSNP: rs367953471

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115299	SCV000149208	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461478	SCV000543333	uncertain significance	Bloom syndrome	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 907 of the BLM protein (p.Thr907Met). This variant is present in population databases (rs367953471, gnomAD 0.03%). 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: 127492). 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	RCV000566952	SCV000672927	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	The p.T907M variant (also known as c.2720C>T), located in coding exon 13 of the BLM gene, results from a C to T substitution at nucleotide position 2720. The threonine at codon 907 is replaced by methionine, an amino acid with similar properties. This alteration was identified in a patient diagnosed with rhabdomyosarcoma (Byrjalsen A et al. PLoS Genet, 2020 Dec;16:e1009231). This amino acid position is not 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.
Counsyl	RCV000461478	SCV000796754	uncertain significance	Bloom syndrome	2017-12-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000461478	SCV000838979	uncertain significance	Bloom syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818264	SCV002071137	uncertain significance	not specified	2020-12-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.2720C>T, in exon 14 that results in an amino acid change, p.Thr907Met. This sequence change does not appear to have been previously described in patients with BLM-related disorders and has been described in the gnomAD database with a low population frequency of 0.011% (dbSNP rs367953471). The p.Thr907Met change affects a poorly 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.Thr907Met substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr907Met change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000461478	SCV003843102	uncertain significance	Bloom syndrome	2023-03-13	criteria provided, single submitter	clinical testing	The BLM c.2720C>T (p.Thr907Met) missense change has a maximum subpopulation frequency of 0.033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Bloom syndrome.  In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003925113	SCV004738009	uncertain significance	BLM-related disorder	2024-01-05	criteria provided, single submitter	clinical testing	The BLM c.2720C>T variant is predicted to result in the amino acid substitution p.Thr907Met. This variant has been reported with uncertain significance in the heterozygous state in an individual with rhabdomyosarcoma (S1 Data, Byrjalsen A et al. 2020 PubMed ID: 33332384). This variant is reported in 0.033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000461478	SCV001454863	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing