ing, and even laboratory genetics. With respect to CHEK2 variant carriers, NCCN Guidelines state that "The risks for most missense variants are unclear but for some pathogenic/likely pathogenic (P/LP) variants, such as Ile157Thr, the risk for breast cancer (BC) appears to be lower [than for frameshift pathogenic/likely pathogenic variants]. Management should be based on best estimates of cancer risk for the specific pathogenic/ likely pathogenic variant." This implies that CHEK2 p.Ile157Thr variant is considered by the NCCN Guidelines panel members to be classified as P/LP, and should be reported for risk management (contrary to variants classified as benign/likely benign [B/LB]).Without speculations on variant classification in accordance with American College of Medical Genetics and Genomics/Sherloc guidelines, 2,3 we may state that, first, this variant may be considered as a rare polymorphism (minor allele frequency [MAF] based on ExAC project 0.40%; in comparison: highest MAF across BRCA1/2 P/LP variants at 0.026% [ExAC] for BRCA2 p.Ser1982fs and the second highest MAF at 0.0067% [ExAC] for BRCA2 p.Cys61Gly, which are 16 times and 60 times higher than MAF for the CHEK2 p.Ile157Thr variant, respectively). Second, risk for BC associated with this variant appears to be low (as noted by current NCCN Guidelines, odds ratio [OR] for BC, 1.58; 95% CI, 1.42-1.75). 4 These put this variant in line with other rare polymorphisms, which, despite B/LB classification (as of majority of CLINVAR submissions), may confer increased risk for BC (though significantly lower, compared with P/LP variants of the same gene). For example, BRCA2

We present a patient with unusual episodes of muscular weakness due to homozygous deletion of exon 2 in the MICU1 gene. Forty-three patients from 33 families were previously described with homozygous and compound heterozygous, predominantly loss of function (LoF) variants in the MICU1 gene that lead to autosomal recessive myopathy with extrapyramidal signs. Most described patients developed muscle weakness and elevated CK levels, and half of the patients had progressive extrapyramidal signs and learning disabilities. Our patient had a few severe acute episodes of muscle weakness with minimal myopathy features between episodes and a strongly elevated Creatinine Kinase (CK). Whole exome sequencing (WES) was performed and the homozygous deletion of exon 2 was suspected. To validate the diagnosis, we performed an RNA analysis of all family members. To investigate the possible impact of this deletion on the phenotype, we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated MICU1 protein that could partly interact with MCU protein in a mitochondrial Ca2+ complex. We suspect that this unusual phenotype of the proband with MICU1-related myopathy could be explained by the presence of the truncated but partly functional protein. This work helps to define the clinical polymorphism of MICU1 deficiency better.

Background Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state. Case presentation We report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities. Conclusions Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.

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e18623 Background: As precision oncology evolves, a growing number of physicians refer cancer patients for CTMP. Oftentimes, CTMP cannot be performed at local centers and patients turn to third-party facilities or commercial solutions. CTMP findings summarized in molecular profiling reports are used by physicians as a basis for MTB. Methods: A molecular tumor board was developed at our cancer center for patients who had undergone CTMP via NGS. Before each MTB, experts in cancer biology and bioinformatics performed reported alteration annotation, interpretation and critical evidence evaluation for each patient, not taking into account the recommendations provided in the original CTMP reports. Results: In total, 29 patients with various tumor types (31% CRC, 25% NSCLC, 10% SOC, 8% Breast; 26% other) who had undergone CTMP in a third-party for-profit organization (2 international, 4 Russian based organizations) were evaluated for discussion at MTB. In 4 CTMP reports therapy recommendations were compiled at odds with principles of evidence-based medicine and did not contain information on detected molecular alteration and, thus, these patients were not discussed within MTB. In 48% (12/25) of reports discussed within MTB, ranking of genomic findings based on potential clinical evidence and actionability was not provided. 24% (6/25) of the reports did not comply with the ASCO recommendations on genomic findings reporting in oncology. In 8 (32%) reports, only drug classes and not specific drugs were recommended. A total of 362 alterations were identified in 25 CTMP reports. Of those, 93 (26%) were not annotated according to the well-established HGVS nomenclature of sequence variants. Out of these 93, 32 (34%) could not be further identified using various genomic tools. Following our interpretation of the reported variants, 16 (4.4%) of the reported variants were found to be benign and, in fact, well-established population polymorphisms (gnomAD MAF > 1%). Only in 40% (10/25) of the reports, genomic alterations were classified based on their origin (somatic/likely germline). For 10 patients, 18 additional therapy options were recommended. Finally, 3-4 hours of preparatory work was required in order to reevaluate the reported findings following CTMP. Conclusions: As tumor molecular profiling becomes a more available tool for precision oncology, the number of patients requiring treatment strategy correction increases. Specific treatment plans can be set up following a discussion within a multidisciplinary team at MTB. Due to the lack of standardization of molecular profiling reporting, thorough preparatory work by experts trained in cancer biology is required before each MTB. Such preliminary work ensures time efficient discussion at MTB, requiring no more than 15 minutes of the physician’s time.