Submissions for variant NM_000057.4(BLM):c.1701G>A (p.Trp567Ter)

dbSNP: rs1356090839

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012779	SCV001173279	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	The p.W567* pathogenic mutation (also known as c.1701G>A), located in coding exon 6 of the BLM gene, results from a G to A substitution at nucleotide position 1701. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been previously identified in an individual with Bloom syndrome in conjunction with another truncating alteration (p.R364*); phase (cis or trans) of the two alterations was not determined (German J et al. Hum. Mutat., 2007 Aug;28:743-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194354	SCV001363839	likely pathogenic	Bloom syndrome	2021-10-20	criteria provided, single submitter	clinical testing	Variant summary: BLM c.1701G>A (p.Trp567X) 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. The variant was absent in 216282 control chromosomes. c.1701G>A has been reported in the literature in a compound heterozygote individual affected with Bloom Syndrome (German_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001194354	SCV002159804	pathogenic	Bloom syndrome	2024-09-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp567*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Bloom syndrome (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 819865). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001194354	SCV004210913	pathogenic	Bloom syndrome	2023-03-16	criteria provided, single submitter	clinical testing
GeneDx	RCV004720034	SCV005325622	pathogenic	not provided	2024-01-04	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); Observed in an individual with Bloom syndrome who harbored a second truncating variant in the BLM gene; however, it is unknown whether the variants were on the same or opposite chromosomes (in cis or trans) (PMID: 17407155); This variant is associated with the following publications: (PMID: 25525159, 26247052, 35448200, 17407155)