Submissions for variant NM_000057.4(BLM):c.768_769CT[2] (p.Leu258fs) (rs367543013)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000034918	SCV000220377	likely pathogenic	Bloom syndrome	2014-06-04	criteria provided, single submitter	literature only
Integrated Genetics/Laboratory Corporation of America	RCV000034918	SCV000694481	pathogenic	Bloom syndrome	2017-04-24	criteria provided, single submitter	clinical testing	Variant summary: The BLM c.772_773delCT (p.Leu258Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent BLM 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.Tyr736fs) and c.1642C>T (p.Gln548X)). One in silico tool predicts a damaging outcome for this variant. This variant was found in 5/119222 control chromosomes at a frequency of 0.0000419, which does not exceed the estimated maximal expected allele frequency of a pathogenic BLM variant (0.0035355). The variant has been reported in at least one homozygous affected individual in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as "pathogenic."
Invitae	RCV000034918	SCV000749564	pathogenic	Bloom syndrome	2019-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu258Glufs*7) in the BLM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs760209332, ExAC 0.03%). This variant has been reported as homozygous in an individual affected with Bloom syndrome (PMID: 17407155). It has also been reported in individuals affected with breast and ovarian cancer (PMID: 24448499, 28724667). This variant is also known as c.768_769del, p.D256fs in the literature. ClinVar contains an entry for this variant (Variation ID: 42092). Loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). For these reasons, this variant has been classified as Pathogenic.

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