Submissions for variant NM_000057.4(BLM):c.2695C>T (p.Arg899Ter)

gnomAD frequency: 0.00004  dbSNP: rs587779884

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115298	SCV000149207	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29453417, 28832562, 29753700, 31959344, 18401830, 26358404, 17407155, 23552953, 27356891, 23225144, 23028338, 28529015, 34426522, 25525159, 31589614, 34117267)
Counsyl	RCV000169191	SCV000220436	likely pathogenic	Bloom syndrome	2014-06-20	criteria provided, single submitter	literature only
Invitae	RCV000169191	SCV000543330	pathogenic	Bloom syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg899*) in the BLM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant is present in population databases (rs587779884, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bloom syndrome and breast cancer (PMID: 17407155, 23028338, 23552953, 26358404, 27356891). ClinVar contains an entry for this variant (Variation ID: 127491). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000115298	SCV000854924	pathogenic	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169191	SCV000893390	pathogenic	Bloom syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169191	SCV000915702	pathogenic	Bloom syndrome	2017-04-28	criteria provided, single submitter	clinical testing	The BLM c.2695C>T (p.Arg899Ter) variant is a stop-gained variant that has been reported in two studies in which it is found in a total of ten patients with Bloom syndrome, including three homozygotes, one compound heterozygote, and six heterozygotes (German et al. 2007; Classen et al. 2013). In one study, the p.Arg899Ter variant was shown to be inherited from an unaffected father (Classen et al. 2013). In addition, the p.Arg899Ter variant has also been reported in a heterozygous state in two individuals with colorectal cancer and in one individual with breast cancer (Thompson et al. 2012; de Voer et al. 2015). The p.Arg899Ter variant was absent from 996 controls, but is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg899Ter variant is classified as pathogenic for Bloom syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169191	SCV000918651	pathogenic	Bloom syndrome	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2695C>T (p.Arg899X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.6e-05 in 121404 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BLM causing Bloom Syndrome (6.6e-05 vs 0.0035), allowing no conclusion about variant significance. c.2695C>T has been reported in the literature in multiple individuals affected with Bloom Syndrome, in both the homozygous and heterozygous state (Classen_2013, German_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001016333	SCV001177280	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	clinical testing	The p.R899* pathogenic mutation (also known as c.2695C>T), located in coding exon 13 of the BLM gene, results from a C to T substitution at nucleotide position 2695. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been identified in both the homozygous state and compound heterozygous state, with another pathogenic BLM mutation, in multiple individuals with Bloom syndrome (German J et al. Hum. Mutat. 2007 Aug;28:743-53; Classen CF et al. Hum. Genet. 2013 Jul;132:825-41; Schoenaker MHD et al. J Clin Immunol. 2018 01;38:35-44). This alteration has also been identified in the heterozygous state in one individual with a personal history of breast cancer, as well as in individuals with colon cancer (Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894; de Voer RM et al. Sci Rep. 2015 Sep;5:14060; Belhadj S et al. Hum Mutat. 2020 09;41:1563-1576). The p.R899* pathogenic mutation has also been detected in the germline of a child diagnosed with a medulloblastoma (Waszak SM et al. Lancet Oncol. 2018 Jun;19:785-798). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000169191	SCV001525674	pathogenic	Bloom syndrome	2018-05-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with Bloom syndrome [PMID 17407155, 23552953, 28832562, 23028338, 25525159]
Revvity Omics, Revvity	RCV000169191	SCV002018407	pathogenic	Bloom syndrome	2019-03-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115298	SCV002069103	pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BLM gene demonstrated a sequence change, c.2695C>T, that results in the creation of a premature stop codon at amino acid position 899, p.Arg899*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BLM protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.014%in the non-Finnish European subpopulation (dbSNP rs587779884). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in individuals with Bloom syndrome (PMID: 23552953, 17407155). Additionally, this pathogenic sequence change has been identified in the heterozygous state in individuals with breast cancer, colon cancer and medulloblastoma (PMID: 23028338, 26358404, 27356891, 29753700). Collectively, these evidences indicate this sequence change is pathogenic.
Sema4, Sema4	RCV001016333	SCV002529470	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000169191	SCV004100572	pathogenic	Bloom syndrome		criteria provided, single submitter	clinical testing	The stop gained p.R899* in BLM (NM_000057.4) has been reported as a recurrent mutation observed as homozygous and compound heterozygous in individuals with Bloom syndrome (German J et al). It has also been reported in individuals with breast cancer (Thompson ER et al) and colon cancer (de Voer RM et al). The p.R899* variant is observed in 16/1,13,728 (0.0141%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The has been reported to ClinVar as Pathogenic/Likely Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000115298	SCV001808979	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000115298	SCV001927665	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000115298	SCV001953352	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000115298	SCV001976118	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169191	SCV002088105	pathogenic	Bloom syndrome	2017-03-16	no assertion criteria provided	clinical testing