Harmonization of variant pathogenicity classification across laboratories is important for advancing clinical genomics. The two CLIAaccredited Electronic Medical Record and Genomics Network sequencing centers and the six CLIA-accredited laboratories and one research laboratory performing genome or exome sequencing in the Clinical Sequencing Evidence-Generating Research Consortium collaborated to explore current sources of discordance in classification. Eight laboratories each submitted 20 classified variants in the ACMG secondary finding v.2.0 genes. After removing duplicates, each of the 158 variants was annotated and independently classified by two additional laboratories using the ACMG-AMP guidelines. Overall concordance across three laboratories was assessed and discordant variants were reviewed via teleconference and email. The submitted variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and cardiac (27%) risk genes. Eighty-six (54%) variants reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance that could affect clinical recommendations (P/LP versus VUS/LB/B). 21% and 63% of variants submitted as P and LP, respectively, were discordant with VUS. Of the 54 originally discordant variants that underwent further review, 32 reached agreement, for a post-review concordance rate of 84% (118/140 variants). This project provides an updated estimate of variant concordance, identifies considerations for LP classified variants, and highlights ongoing sources of discordance. Continued and increased sharing of variant classifications and evidence across laboratories, and the ongoing work of ClinGen to provide general as well as gene-and disease-specific guidance, will lead to continued increases in concordance.

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The descriptor ‘usual care’ refers to standard or routine care. Yet, no formal definition exists. The need to define what constitutes usual care arises in clinical research. Often one arm in a trial represents usual care in comparison with a novel intervention. Accordingly, usual care in genetic counseling research appears predominantly in randomized controlled trials. Recent standards for reporting genetic counseling research call for standardization, but do not address usual care. We (1) inventoried all seven studies in the Clinical Sequencing Evidence‐Generating Consortium (CSER) about how genetic counseling was conceptualized, conducted, and whether a usual care arm was involved; (2) conducted a review of published randomized control trials in genetic counseling, comparing how researchers describe usual care groups; and (3) reviewed existing professionally endorsed definitions and practice descriptions of genetic counseling. We found wide variation in the content and delivery of usual care. Descriptions frequently detailed the content of usual care, most often noting assessment of genetic risk factors, collecting family histories, and offering testing. A minority included addressing psychological concerns or the risks versus benefits of testing. Descriptions of how care was delivered were vague except for mode and type of clinician, which varied. This significant variation, beyond differences expected among subspecialties, reduces the validity and generalizability of genetic counseling research. Ideally, research reflects clinical practice so that evidence generated can be used to improve clinical outcomes. To address this objective, we propose a definition of usual care in genetic counseling research that merges common elements from the National Society of Genetic Counselors’ practice definition, the Reciprocal Engagement Model, and the Accreditation Council for Genetic Counselors’ practice‐based competencies. Promoting consistent execution of usual care in the design of genetic counseling trials can lead to more consistency in representing clinical care and facilitate the generation of evidence to improve it.

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Dementing illnesses are progressive, neurodegenerative conditions most commonly occurring sporadically after age 65. A subset of dementia cases, however, are hereditary (Bekris et al., 2010) and have been shown to be caused by pathogenic variants in genes such as PSEN1, PSEN2, APP, GRN, and MAPT (Blue et al., 2018) and by C9orf72 GGGGCC hexanucleotide repeat expansions (Lee et al., 2014). Still, many familial cases remain unsolved by genetic testing and are not sufficiently explained by known risk alleles, such

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The objective of this study was to identify interpretation challenges specific to exome sequencing and errors of potential clinical significance in the context of genetic counseling for adults at risk for a hereditary cancer syndrome. Thirty transcripts of interpreter‐mediated telephone results disclosure genetic counseling appointments were coded for errors by bilingual researchers, and the coders applied an overall rating to denote the degree to which the errors interfered with communication overall. Genetic counselors reviewed a subset of errors flagged for potential clinical significance to identify those likely to have clinical impact. Qualitative interviews with 19 interpreters were analyzed to elucidate the challenges they face in interpreting for genetic counseling appointments. Our analysis identified common interpretation errors such as raising the register, omissions, and additions. Further, we found errors specific to genetic counseling concepts and content that appeared to impact the ability of the genetic counselor to accurately assess risk. These errors also may have impacted the patient's ability to understand their results, access appropriate follow‐up care, and communicate with family members. Among interpreters' strengths was the use of requests for clarification; in fact, even more use of clarification would have been beneficial in these encounters. Qualitative interviews surfaced challenges stemming from the structure of interpreter work, such as switching from medical and nonmedical interpretations without substantial breaks. Importantly, while errors were frequent, most did not impede communication overall, and most were not likely to impact clinical care. Nevertheless, potentially clinically impactful errors in communication of genetics concepts may contribute to inequitable care for limited English proficient patients and suggest that additional training in genetics and specialization in healthcare may be warranted. In addition, training for genetic counselors and guidance for patients in working effectively with interpreters could enhance interpreters' transmission of complex genetic concepts.

Biallelic mutations in POLR3A have been associated with childhood‐onset hypomyelinating leukodystrophies and adolescent‐to‐adult‐onset spastic ataxia, the latter of which has been linked to the intronic variant c.1909 + 22G>A. We report a case of adult‐onset spastic ataxia in a 75‐year‐old man, being a compound heterozygous carrier of this variant, whose brain and spinal cord were for the first time investigated by neuropathological examination. We describe prominent degeneration of the posterior columns, spinocerebellar tracts, and anterior corticospinal tracts of the spinal cord in a pattern resembling Friedreich's ataxia, with a notable lack of significant white matter pathology throughout the brain, in marked contrast with childhood‐onset cases. Immunohistochemical examination for the POLR3A protein demonstrated no apparent differences in localization or staining intensity between the proband and an age‐matched control subject. We demonstrate the clinicopathologic description of POLR3A‐related neurodegenerative disease and also mention the differential diagnosis of the childhood‐onset hypomyelinating leukodystrophy and late‐onset spastic ataxia phenotypes.