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Purpose The 2015 American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification. Methods We undertook an iterative process of refining the ACMG–AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases. During this process, the criteria evolved through eight major and minor revisions. Results Our implementation: (i) separated ambiguous ACMG–AMP criteria into a set of discrete but related rules with refined weights; (ii) grouped certain criteria to protect against the overcounting of conceptually related evidence; and (iii) replaced the “clinical criteria” style of the guidelines with additive, semiquantitative criteria. Conclusion Sherloc builds on the strong framework of 33 rules established by the ACMG–AMP guidelines and introduces 108 detailed refinements, which support a more consistent and transparent approach to variant classification.

Objectives: Chronic pelvic pain is the third most frequently cited indication for hysterectomy in the United States. The purpose of the present study was to investigate the relationship between prior hysterectomy and somatization in 155 consecutive referrals to a multidisciplinary chronic pelvic pain clinic at the University of Iowa. Study Design: All subjects completed a baseline evaluation assessing pain and medical history, demographic variables, abuse history, and family history of chronic pain. All subjects also completed the Beck Depression Inventory (BDI), the West Haven Yale Multi-Dimensional Pain Inventory (WHYMPI), the Locke-Wallace Marital Adjustment Scale, a previously validated somatization check-list, and an open-ended experimental item assessing attributions of pain causality. Thirty (20%) of the referrals who had previously undergone hysterectomy with or without bilateral salpingooophorectomy prior to referral to the clinic (study group) were compared with 125 subjects who had uteri and at least one adnexa in situ (controls). All dichotomous comparisons and tests for trends used a x2, 1 test, or Fisher’s exact test as appropriate. Results: Women who had undergone previous hysterectomy were found to be significantly older than women in the control group. Somatization scores were significantly higher among women in the study group as compared with controls. In addition, women who had undergone hysterectomy were significantly more likely to attribute their pain to occult somatic conditions (gynecological or other medical) than were control subjects. No differences were observed in demographic variables, spouse responses or marital adjustment, mood, severity or duration of pain, perceived control, physical or sexual abuse histories, or functional status between women in the study and control groups. Conclusions: These data suggest that hysterectomy may be regarded as a possible outcome of somatization and somatic causal pain attributions. They should serve to alert clinicians to women who may be at increased risk for atypical health care seeking behaviors, including surgery-seeking. They also emphasize the importance of comprehensive, multidisciplinary evaluation in women with chronic pelvic pain and women in whom hysterectomy is being considered in particular .