Submissions for variant NM_000057.4(BLM):c.2333C>G (p.Ser778Cys)

gnomAD frequency: 0.00012  dbSNP: rs139610577

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656782	SCV000149200	uncertain significance	not provided	2021-06-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a 2-year-old male with short telomeres, bone marrow failure, hepatosplenomegaly, and increased transaminases (Arias-Salgado EG et al., 2019); This variant is associated with the following publications: (PMID: 30995915, 27535533)
Invitae	RCV001080005	SCV000283123	benign	Bloom syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115291	SCV000593635	uncertain significance	not specified	2016-11-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562292	SCV000672906	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	The p.S778C variant (also known as c.2333C>G), located in coding exon 10 of the BLM gene, results from a C to G substitution at nucleotide position 2333. The serine at codon 778 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was not found to show hypersensitivity to the DNA damaging agent hydroxyurea, as compared to the wild-type allele, in a humanized yeast model (Mirzaei H et al. Proc. Natl. Acad. Sci. U.S.A., 2012 Nov;109:19357-62). This alteration was identified in an individual at an increased risk of hereditary breast and/or ovarian cancer syndrome (HBOC) (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001080005	SCV001279005	uncertain significance	Bloom syndrome	2017-10-04	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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	RCV000115291	SCV001448502	uncertain significance	not specified	2020-11-27	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2333C>G (p.Ser778Cys) results in a non-conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251474 control chromosomes, predominantly found in the Ashkenazi Jewish subpopulation with a frequency of 0.0025. This frequency is somewhat lower than the expected maximum for a pathogenic variant pathogenic variant in BLM causing Bloom Syndrome (0.0035), allowing no clear conclusion about variant significance. The variant, c.2333C>G, has been reported in the literature in heterozygous state in individuals affected with colorectal cancer (Martin-Morales_2018), personal and/or family history of breast/ovarian cancer (Bonache_2018), and in a patient affected with dyskeratosis congenita/aplastic anemia (Arias-Salgado_2019), however no strong evidence for causality was noted. These reports do not provide unequivocal conclusions about association of the variant with Bloom Syndrome. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect of this variant in a yeast based DNA-damaging agent sensitivity assay (Mirzaei_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656782	SCV002010763	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562292	SCV002529348	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001080005	SCV002584767	uncertain significance	Bloom syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The BLM c.2333C>G (p.Ser778Cys) missense change has a maximum non-founder subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, however the variant did not demonstrate hypersensitivity as compared to the wild-type in a yeast-based DNA-damage assay suggesting that it may be neutral (PMID: 23129629). This variant has been reported in individuals affected with colorectal cancer (PMID: 30256826), personal and/or family history of breast/ovarian cancer (PMID: 30306255), and dyskeratosis congenita (PMID: 30995915). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000656782	SCV004130908	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BLM: PM2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115291	SCV004242658	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing