Submissions for variant NM_000057.4(BLM):c.543C>A (p.Ser181Arg)

dbSNP: rs761288442

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472724	SCV000543329	uncertain significance	Bloom syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 181 of the BLM protein (p.Ser181Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 405277). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Mendelics	RCV003492048	SCV000838948	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024105	SCV001186064	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The p.S181R variant (also known as c.543C>A), located in coding exon 2 of the BLM gene, results from a C to A substitution at nucleotide position 543. The serine at codon 181 is replaced by arginine, an amino acid with dissimilar properties. 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.
Natera, Inc.	RCV000472724	SCV001456642	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745390	SCV005351329	uncertain significance	BLM-related disorder	2024-09-01	no assertion criteria provided	clinical testing	The BLM c.543C>A variant is predicted to result in the amino acid substitution p.Ser181Arg. This variant was reported as a variant of uncertain significance in 12 Brazilian breast cancer patients (Supplementary Table 3. Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.0061% of alleles in individuals of Latino descent in gnomAD and has conflicting classifications of pathogenicity in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/405277/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.