Submissions for variant NM_000057.4(BLM):c.715G>A (p.Asp239Asn)

gnomAD frequency: 0.00006  dbSNP: rs200756519

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656778	SCV000149232	uncertain significance	not provided	2014-01-22	criteria provided, single submitter	clinical testing	Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.715G>A at the cDNA level, p.Asp239Asn (D239N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Asp239Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution in which a negative polar amino acid is replaced with a neutral polar one, altering a position that is moderately conserved throughout evolution and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider BLM Asp239Asn to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472713	SCV000543392	uncertain significance	Bloom syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 239 of the BLM protein (p.Asp239Asn). This variant is present in population databases (rs200756519, 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: 127515). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV000570925	SCV000672948	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The p.D239N variant (also known as c.715G>A), located in coding exon 2 of the BLM gene, results from a G to A substitution at nucleotide position 715. The aspartic acid at codon 239 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS ONE. 2014 Apr;9:e94554). 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.
Counsyl	RCV000472713	SCV000788545	uncertain significance	Bloom syndrome	2017-12-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000472713	SCV002584611	uncertain significance	Bloom syndrome	2022-09-02	criteria provided, single submitter	clinical testing	The BLM c.715G>A (p.Asp239Asn) missense change has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, and to our knowledge functional studies have not been performed. This variant has been observed in individuals with acute myeloid leukemia, colorectal cancer, pancreatic cancer, glioblastoma and medulloblastoma (PMID: 28944238, 29338072, 29467491, 29487696, 30840646, 31676785, 31747416). 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.
ITMI	RCV000120240	SCV000084388	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252890	SCV001164033	uncertain significance	Microcephaly		no assertion criteria provided	research