Submissions for variant NM_000057.4(BLM):c.2098C>T (p.Gln700Ter)

gnomAD frequency: 0.00002  dbSNP: rs367543028

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000317685	SCV000329113	pathogenic	not provided	2022-05-18	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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28232778, 26786923, 29625052, 26689913, 17407155)
Invitae	RCV000034893	SCV000543350	pathogenic	Bloom syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln700*) 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 (rs367543028, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 42067). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034893	SCV000916688	pathogenic	Bloom syndrome	2018-09-14	criteria provided, single submitter	clinical testing	Variant summary: BLM c.2098C>T (p.Gln700X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2207_2212delinsTAGATTC (p.Tyr736fsX5) and c.2695C>T (p.Arg899X)). The variant allele was found at a frequency of 1.1e-05 in 277168 control chromosomes (gnomAD). c.2098C>T has been reported in the literature, in homozygosity or compound heterozygosity, in multiple individuals affected with Bloom Syndrome (German_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the variant impact. The most pronounced variant effect in homozygous individuals resulted in <20% mRNA amount compared to normal, based on Northern blot analyses (German_2007). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001014425	SCV001175127	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	clinical testing	The p.Q700* pathogenic mutation (also known as c.2098C>T), located in coding exon 8 of the BLM gene, results from a C to T substitution at nucleotide position 2098. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been reported in both a homozygous and compound heterozygous state in multiple individuals with Bloom syndrome (German J et al. Hum. Mutat., 2007 Aug;28:743-53). 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.
Revvity Omics, Revvity	RCV000034893	SCV002018440	pathogenic	Bloom syndrome	2022-03-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000034893	SCV004210893	pathogenic	Bloom syndrome	2023-05-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000034893	SCV000485410	pathogenic	Bloom syndrome	2015-12-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000034893	SCV002088031	pathogenic	Bloom syndrome	2017-03-16	no assertion criteria provided	clinical testing