Submissions for variant NM_000057.4(BLM):c.2839A>G (p.Ile947Val)

gnomAD frequency: 0.00010  dbSNP: rs189925962

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541196	SCV000623292	likely benign	Bloom syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016575	SCV001177541	likely benign	Hereditary cancer-predisposing syndrome	2021-07-01	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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030457	SCV001193517	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000541196	SCV001273602	uncertain significance	Bloom syndrome	2017-04-27	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194357	SCV001363843	uncertain significance	not specified	2022-02-24	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2839A>G (p.Ile947Val) results in a conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251454 control chromosomes, predominantly at a frequency of 0.0027 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (0.00021 vs 0.0035), allowing no conclusion about variant significance. c.2839A>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with/undergoing testing for a variety of cancers (example, Kim_2019, Park_2018, Zhang_2019). These report(s) do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sema4, Sema4	RCV001016575	SCV002531783	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153670	SCV003843819	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478099	SCV004222465	likely benign	not provided	2022-09-26	criteria provided, single submitter	clinical testing