Submissions for variant NM_000057.4(BLM):c.4220G>A (p.Arg1407Lys)

gnomAD frequency: 0.00023  dbSNP: rs557057587

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543803	SCV000623335	benign	Bloom syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022081	SCV001183775	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.R1407K variant (also known as c.4220G>A), located in coding exon 21 of the BLM gene, results from a G to A substitution at nucleotide position 4220. The arginine at codon 1407 is replaced by lysine, an amino acid with highly similar properties. This alteration has been reported in two unrelated Puerto Rican breast cancer patients that met clinical criteria for BRCA testing and had previously tested negative for mutations in the BRCA1/BRCA2 genes (Dutil J et al. Sci Rep, 2019 Nov;9:17769). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002476078	SCV002774444	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 31780696 (2019)) and head/neck cancer (PMID: 32449991 (2020)). The frequency of this variant in the general population, 0.00025 (9/35440 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV002476078	SCV003924704	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Dutil et al., 2019); This variant is associated with the following publications: (PMID: 31780696, 32449991)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000543803	SCV004031195	uncertain significance	Bloom syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The BLM c.4220G>A (p.Arg1407Lys) missense change has a maximum subpopulation frequency of 0.025% 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. This variant has been reported in individuals with BRCA1/2-negative breast cancer (PMID: 31780696) and in 1 of 473 mismatch repair-proficient familial/early-onset colorectal cancer proband (PMID: 32449991). 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.
Natera, Inc.	RCV000543803	SCV001461032	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing