ClinVar Miner

Submissions for variant NM_000057.4(BLM):c.2695C>T (p.Arg899Ter) (rs587779884)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115298 SCV000149207 pathogenic not provided 2016-09-15 criteria provided, single submitter clinical testing Single pathogenic variants in BLM have only recently been described in association with cancer predispositionand the risks are not well understood. This is a nonsense variant, denoted BLM c.2695C>T at the cDNA level and p.Arg899Ter (R899X) at the protein level. The substitution creates a nonsense variant, changing an Arginine to a premature stop codon (CGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BLM 2695C>T has been published as a mutation in association with Bloom syndrome (German 2007) and in association with breast cancer (Thompson 2012). Therefore, we consider this a pathogenic variant, and this individual is a carrier of Bloom syndrome, a recessive condition characterized by short stature, skin changes in response to sun exposure, and increased cancer risk. One variant in the BLM gene has been estimated to increase the risk of female breast cancer and colon cancer although there are conflicting reports. A recent meta-analysis estimated the odds ratio for breast cancer to be 2.5 (Sokolenko 2012) which translates to a lifetime risk of approximately 30%. Approximately 1% of individuals of Ashkenazi Jewish descent are carriers of the BLM founder pathogenic variant, c.2207_2212delinsTAGATTC (Ellis 1998). A 2.5-fold increased risk of colon cancer has been described in individuals carrying this specific mutation which amounts to approximately 13% lifetime risk (Gruber 2002). Of note, Cleary et al (2003) did not find evidence of increased cancer risk in carriers of this BLM founder pathogenic variant.
Counsyl RCV000169191 SCV000220436 likely pathogenic Bloom syndrome 2014-06-20 criteria provided, single submitter literature only
Invitae RCV000169191 SCV000543330 pathogenic Bloom syndrome 2020-10-25 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. This variant is present in population databases (rs587779884, ExAC 0.01%). This variant has been reported as a recurrent mutation observed as homozygous and compound heterozygous in individuals with Bloom syndrome (PMID: 17407155, 23552953). It has also been reported in individuals with breast cancer (PMID: 23028338) and colon cancer (PMID: 26358404, 27356891). ClinVar contains an entry for this variant (Variation ID: 127491). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Clinical Services Laboratory,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 2018-12-20 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). This alteration has also been identified in the heterozygous state in one individual with a personal history of breast cancer, as well as two 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). 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]
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000115298 SCV001808979 pathogenic not provided no assertion criteria provided clinical testing

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