Submissions for variant NM_000057.4(BLM):c.2069C>T (p.Pro690Leu)

dbSNP: rs761589072

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000535832	SCV000623257	uncertain significance	Bloom syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 690 of the BLM protein (p.Pro690Leu). This variant is present in population databases (rs761589072, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 17407155, 30871259). ClinVar contains an entry for this variant (Variation ID: 454092). 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 expected to disrupt BLM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BLM function (PMID: 2678854, 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.
Counsyl	RCV000535832	SCV000793320	uncertain significance	Bloom syndrome	2017-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420335	SCV002725661	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-14	criteria provided, single submitter	clinical testing	The p.P690L variant (also known as c.2069C>T), located in coding exon 7 of the BLM gene, results from a C to T substitution at nucleotide position 2069. The proline at codon 690 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in the heterozygous state in an individual with Bloom syndrome. The presence of another BLM alteration in this individual is not mentioned by study authors (German J et al. Hum. Mutat., 2007 Aug;28:743-53). This alteration has demonstrated functional impairment with respect to chromosome maintenance, DNA damage response and sensitivity to DNA damaging agents (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62; Shastri VM et al. Mol Genet Genomic Med, 2016 Jan;4:106-19). This alteration has also been identified in the germline of an individual from a familial colorectal cancer cohort that underwent whole exome sequencing (Díaz-Gay M et al. Cancers (Basel), 2019 03;11:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003228941	SCV003925990	uncertain significance	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies support a damaging effect: hypersensitivity to hydroxyurea (HU) and no significant reduction in SCE frequency or formation of quadriradical chromosomes (Mirzaei et al., 2012; Shastri et al., 2016); Observed in individuals with a personal or family history of colorectal cancer (Daz-Gay et al., 2019); This variant is associated with the following publications: (PMID: 24816114, 30871259, 17407155, 23129629, 26788541, 32704157)
Natera, Inc.	RCV000535832	SCV001461833	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing