Submissions for variant NM_000057.4(BLM):c.3970C>T (p.His1324Tyr)

gnomAD frequency: 0.00001  dbSNP: rs748943489

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548110	SCV000623324	uncertain significance	Bloom syndrome	2022-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1324 of the BLM protein (p.His1324Tyr). This variant is present in population databases (rs748943489, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Bloom syndrome (PMID: 17407155, 31159747). ClinVar contains an entry for this variant (Variation ID: 454145). 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 does not substantially affect BLM function (PMID: 17407155). 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.
GeneKor MSA	RCV000708669	SCV000821906	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708669	SCV001183184	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.H1324Y variant (also known as c.3970C>T), located in coding exon 20 of the BLM gene, results from a C to T substitution at nucleotide position 3970. The histidine at codon 1324 is replaced by tyrosine, an amino acid with similar properties. This variant has been identified in one person with Bloom Syndrome and functional studies have shown that it preserves normal BLM protein function in reducing the levels of sister-chromatid exchanges in patient-derived cells (German J et al. Hum. Mutat., 2007 Aug;28:743-53; Perreault-Micale C et al. Mol Genet Genomic Med, 2015 Jul;3:363-73). Another study determined that this variant (reported as c.3970C>T, p.H1324T) was not sensitive to the DNA damaging agent, hydroxyurea, similar to wildtype (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This variant was also reported as a variant of unknown signifcance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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.
GeneDx	RCV002281102	SCV002569600	uncertain significance	not provided	2022-02-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing genetic testing for hereditary cancer predisposition and in an individual with Bloom syndrome in published literature (German 2007, Tsaousis 2019); Published functional studies suggest no damaging effect: reduced levels of sister-chromatid exchanges (German 2007); This variant is associated with the following publications: (PMID: 26247052, 31159747, 17407155)
Natera, Inc.	RCV000548110	SCV001456914	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing