Submissions for variant NM_000057.4(BLM):c.4068G>C (p.Lys1356Asn)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115317	SCV000149226	uncertain significance	not provided	2014-05-08	criteria provided, single submitter	clinical testing	Single pathogenic variants in BLM have only recently been described in association with cancer predisposition and the risks are not well understood. This variant is denoted BLM c.4068G>C at the cDNA level, p.Lys1356Asn (K1356N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BLM Lys1356Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. BLM Lys1356Asn occurs at a position that is highly variable across species and is not located within any known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BLM Lys1356Asn is pathogenic or benign. We consider it to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and with single variants the BLM gene in general, remain unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001831903	SCV002165483	uncertain significance	Bloom syndrome	2021-04-28	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 127509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 1356 of the BLM protein (p.Lys1356Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine.
Natera, Inc.	RCV001831903	SCV002090644	uncertain significance	Bloom syndrome	2020-11-02	no assertion criteria provided	clinical testing

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