ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2362C>A (p.Leu788Ile)

gnomAD frequency: 0.00086  dbSNP: rs149754073
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115292 SCV000149201 uncertain significance not provided 2020-03-07 criteria provided, single submitter clinical testing Observed in individuals with a personal history of breast cancer (Thompson et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23028338)
Invitae RCV001082972 SCV000555825 benign Bloom syndrome 2024-01-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564057 SCV000672895 likely benign Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Illumina Laboratory Services, Illumina RCV001082972 SCV001279006 likely benign Bloom syndrome 2017-05-22 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV001818263 SCV002069614 uncertain significance not specified 2020-01-09 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001082972 SCV004031129 uncertain significance Bloom syndrome 2023-05-31 criteria provided, single submitter clinical testing The BLM c.2362C>A (p.Leu788Ile) missense change has a maximum subpopulation frequency of 0.081% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in one individual with breast cancer (PMID: 23028338), and in cases with Langerhans cell histiocytosis (PMID: 33332384), colorectal cancer (PMID: 28944238) and one suspected Lynch syndrome (PMID: 32660107). It has also identified in 2 of 1358 control individuals collected as part of non-cancer studies (PMID: 29641532). 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.
Preventiongenetics, part of Exact Sciences RCV003407494 SCV004109020 uncertain significance BLM-related condition 2022-10-21 criteria provided, single submitter clinical testing The BLM c.2362C>A variant is predicted to result in the amino acid substitution p.Leu788Ile. This variant was reported as variant of uncertain significance in an individual with suspected Lynch syndrome, who also carried a missense variant in WRN (Table S1, Olkinuora et al 2020. PubMed ID: 32660107). This variant is also reported in one individual with breast cancer (Table S4, Thompson et al. 2012. PubMed ID: 23028338). The p.Leu788Ile substitution is predicted with neutral effects for stability (Table 2, Sora and Otamendi et al. 2022 (preprint), https://www.biorxiv.org/content/10.1101/2022.09.02.506350v1.full.pdf). This variant is reported in 0.57% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-91312417-C-A). In ClinVar, this variant is interpreted as benign/likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127485/?new_evidence=false). This variant could be benign, however, due to the small cohort sizes we interpret these data as inconclusive. At this time, the clinical significance of this variant is uncertain.
Natera, Inc. RCV001082972 SCV001461105 uncertain significance Bloom syndrome 2017-05-26 no assertion criteria provided clinical testing

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