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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely.METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification.RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score.CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.

Germline pathogenic variants (GPVs) in the cancer predisposition genes

BackgroundGermline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing.MethodsWe designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing ofBRCA1/BRCA2/PALB2(BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway).ResultsUptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with ConclusionPilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses.Trial registration numberISRCTN87845055.

Peer reviewed: True, OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Introduction: Breast cancer is the most common cancer in women. Women with personal history of breast cancer are at increased risk of second primary cancers including ovarian cancer. Bilateral salpingo-oophorectomy (BSO) is a well-established option for ovarian cancer risk reduction. However, the benefit of ovarian cancer risk reduction should be balanced against the health sequelae caused by the premature estrogen loss. We examined the associations between BSO after breast cancer diagnosis and long-term health outcomes, using large-scale linked electronic health records. Methods: We selected women diagnosed with invasive breast cancer before the age of 75 between 1995 and 2019 using data from the National Cancer Registration Dataset (NCRD), which describes all cancers registered in England. These women were linked to the Hospital Episode Statistics (HES) Admitted Patient Care (APC) dataset to identify the delivery of BSO, while the use of hormonal replacement therapy (HRT) was identified from the community dispensed prescriptions dataset. Long-term outcomes (e.g., ischemic heart disease) were selected from HES, and the NCRD provided data on second cancer diagnosis and all-cause mortality. Multiple imputation was used to impute missing data on stage, grade, hormonal receptor status and ethnicity. Women were followed from the date of breast cancer diagnosis to development of an outcome of interest or censoring or end of data collection. Multivariable Cox regression was used to examine the associations, with BSO modeled as a time-dependent covariate. The analysis was stratified by patient age at BSO ( Results: The study included 566,731 women, with median follow up time 8.40 (IQR: 4.4-14.5) years. Of those, 23,881 women had BSO after their breast cancer diagnosis. BSO before the age of 55 was not associated with all-cause mortality (hazard ratio (HR):1.03, 95%CI:0.98-1.08), while BSO after the age of 55 was associated with a small reduction in the risk of all-cause mortality (HR:0.93, 95%CI:0.89-0.99). BSO before and after the age of 55 was associated with increased risk of ischemic heart disease with HRs of 1.23(95%CI:1.07-1.41) and 1.13(95%CI:1.02-1.25), respectively. There was no association between BSO and cerebrovascular events (HR:0.97, 95%CI:0.82-1.15, for BSO under age 55, HR:0.96, 95%CI:0.87-1.07, for BSO after age 55). Ongoing analyses are investigating the associations stratified by the severity of cardiovascular outcome (fatal/non-fatal) and the use of HRT, and the associations with second cancers and neuropsychiatric outcomes. Conclusion: BSO after 55 does not appear to be associated with detrimental health effects in women diagnosed with breast cancer. Further examination of the associations between BSO and other long-term health outcomes and the influence of HRT in younger women is needed. Citation Format: Hend Hassan, Tameera Rahman, Andrew Bacon, Craig Knott, Isaac Allen, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Bethany Torr, Diana M Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Long-term health outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 988.

Background: Second primary cancer (SPC) incidence is rising among breast cancer (BC) survivors, but these risks remain unclear. We estimated SPC risks for male and female BC survivors using large-scale electronic health record data from a linkage of National Cancer Registration and Analysis Service data and Hospital Episode Statistics surgical records in England. Material and Methods: We used a retrospective cohort study design comprising 763,578 female and 4,795 male BC survivors first diagnosed with BC between 1995-2018. We calculated overall and site-specific SPC standardized incidence ratios (SIRs) by comparing observed and expected SPC counts for 19 cancer sites. Study participants were followed from one year after the first BC diagnosis until either a SPC diagnosis (excluding ipsilateral breast and non-melanoma skin cancers), death, migration, relevant surgical procedures, or the end of 2019. Expected SPC counts were calculated using year-, age- and sex-specific cancer incidence rates in the general English population. We stratified the SIRs by age group, sex, and cancer site. We estimated Kaplan-Meier absolute risks of site-specific SPCs and assessed the influence of age at first BC diagnosis using Cox proportional hazards models. Results: There were 68,550 and 720 incident SPCs among female and male BC survivors, respectively. There was a significant increased risk of all SPCs combined for female BC survivors (SIR: 1.19, 95%CI: 1.18-1.20). There were significant increased risks for SPC at all sites combined, all non-breast sites combined, and at 12 further specific sites for females and at 2 specific sites for males. Among females, the increase was greatest for contralateral breast (SIR: 1.82, 95%CI: 1.79-1.85) and uterine cancers (SIR: 1.80, 95%CI: 1.76-1.85). The risk at all sites combined was higher for women first diagnosed with BC before age 50 (SIR: 1.89, 95%CI: 1.85-1.92) compared to women diagnosed with BC at age 50 or over (SIR: 1.11, 95%CI: 1.10-1.12). The largest associations were observed for contralateral breast (SIR: 3.19, 95%CI: 3.11-3.29) and uterine (SIR: 1.77, 95%CI: 1.73-1.82) SPCs in the younger and older age groups, respectively. Increasing age at first female BC diagnosis was associated with decreasing CBC absolute risks, but significantly increased absolute risks of all other SPCs. Male BC survivors were at increased risk of contralateral breast (SIR: 42.39, 95%CI: 28.39-60.89) and prostate (SIR: 1.29, 95%CI: 1.13-1.46) SPCs. Conclusions: This is the largest study to date to assess SPC risks following BC in either men or women. SPC risks were significantly increased, both in combination and at specific sites. These findings could help guide clinical management, such as screening recommendations, for BC survivors. Further analysis is underway to investigate the effects of chemotherapy, radiotherapy, hormonal therapy, comorbidities, or germline BC susceptibility. Citation Format: Isaac Allen, Tameera Rahman, Andrew Bacon, Craig Knott, Sophie Jose, Sally Vernon, Hend Hassan, Catherine Huntley, Lucy Loong, Yvonne Walburga, Katrina Lavelle, Eva Morris, Steven Hardy, Beth Torr, Diana Eccles, Clare Turnbull, Marc Tischkowitz, Paul Pharoah, Antonis C. Antoniou. Second primary cancer risks for female and male breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3057.

Purpose: Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice. Methods: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. Results: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. Conclusion: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioural disturbance and EEG abnormalities. Here, we expand the genotypes and phenotypes and identify discriminating features of this disorder.MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. Evidence for pathogenicity is discussed, including ACMG criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioural data for 14 cases are compared to other monogenic neurodevelopmental disorders.ResultsFour variants lie in the C2A domain with the remainder in the C2B. We classify 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes include delayed developmental milestones, ophthalmic problems, abnormal EEG, movement disorders and sleep disturbance. Discriminating behavioural characteristics were severity of motor and communication impairment, presence of motor stereotypies and mood instability.ConclusionSYT1 variants associated with neurodevelopmental disorder extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severity than initially reported. This work guides diagnosis and molecular understanding of this rare neurodevelopmental disorder, and highlights a key role for SYT1 function in emotional regulation, motor control and emergent cognitive function.

Pathogenic variants in HNRNPH1 were first reported in 2018. The reported individual, a 13 year old boy with a c.616C>T (p.R206W) variant in the HNRNPH1 gene, was noted to have overlapping symptoms with those observed in HNRNPH2-related X-linked intellectual disability, Bain type (MRXSB), specifically intellectual disability and dysmorphic features. While HNRNPH1 variants were initially proposed to represent an autosomal cause of MRXSB, we report an additional seven cases which identify phenotypic differences from MRXSB. Patients with HNRNPH1 pathogenic variants diagnosed via WES were identified using clinical networks and GeneMatcher. Features unique to individuals with HNRNPH1 variants include distinctive dysmorphic facial features; an increased incidence of congenital anomalies including cranial and brain abnormalities, genitourinary malformations, and palate abnormalities; increased incidence of ophthalmologic abnormalities; and a decreased incidence of epilepsy and cardiac defects compared to those with MRXSB. This suggests that pathogenic variants in HNRNPH1 result in a related, but distinct syndromic cause of intellectual disability from MRXSB, which we refer to as HNRNPH1-related syndromic intellectual disability.