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

gnomAD frequency: 0.00086  dbSNP: rs149754073

Total submissions: 8

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082972	SCV000555825	benign	Bloom syndrome	2025-02-04	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: 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.
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.
Natera, Inc.	RCV001082972	SCV001461105	uncertain significance	Bloom syndrome	2017-05-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407494	SCV004109020	likely benign	BLM-related disorder	2024-06-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).