Submissions for variant NM_000057.4(BLM):c.887A>T (p.Tyr296Phe)

dbSNP: rs775005766

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneKor MSA	RCV000708671	SCV000821908	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697513	SCV000826129	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 296 of the BLM protein (p.Tyr296Phe). This variant is present in population databases (rs775005766, gnomAD 0.006%). 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: 575327). 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	RCV000708671	SCV001179673	likely benign	Hereditary cancer-predisposing syndrome	2024-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689860	SCV005185223	uncertain significance	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: BLM c.887A>T (p.Tyr296Phe) results in a conservative amino acid change located in the RecQ-like DNA helicase BLM, N-terminal domain (IPR032437) 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 2.4e-05 in 251272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.887A>T has been reported in the literature in at least one individual with suspected personal or family history of hereditary cancer predisposition without evidence for causality (e.g. Tsaousis_2019). This report does not provide unequivocal conclusions about association of the variant with Bloom Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 575327). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004997187	SCV005624293	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	The BLM c.887A>T (p.Tyr296Phe) variant has been reported in the published literature in an individual with a personal or family history of breast/ovarian cancer (PMID: 31159747 (2019)). The frequency of this variant in the general population, 0.000024 (6/251272 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000697513	SCV005640418	uncertain significance	Bloom syndrome	2024-05-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000697513	SCV001460763	uncertain significance	Bloom syndrome	2020-09-16	no assertion criteria provided	clinical testing