Submissions for variant NM_000057.4(BLM):c.1877A>T (p.Tyr626Phe)

gnomAD frequency: 0.00002  dbSNP: rs374569385

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628657	SCV000749561	uncertain significance	Bloom syndrome	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 626 of the BLM protein (p.Tyr626Phe). This variant is present in population databases (rs374569385, gnomAD 0.005%). 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: 133714). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BLM protein function with a negative predictive value of 80%. 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	RCV001013499	SCV001174092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.Y626F variant (also known as c.1877A>T), located in coding exon 6 of the BLM gene, results from an A to T substitution at nucleotide position 1877. The tyrosine at codon 626 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not 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.
Sema4, Sema4	RCV001013499	SCV002533658	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120247	SCV003934676	uncertain significance	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: BLM c.1877A>T (p.Tyr626Phe) results in a conservative amino acid change located in the BDHCT-box associated domain (IPR032439) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1e-05 in 195556 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1877A>T has been reported in the literature in a cohort of healthy individuals with no personal or family history indicative of a highly penetrant cancer-predisposing germline mutation (Bodian_2014). To our knowledge, no occurrences of the variant in individuals affected with Bloom Syndrome and no experimental evidence demonstrating an impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24728327). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI	RCV000120247	SCV000084396	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000628657	SCV001461828	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing