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Lynch syndrome accounts for 3-5% of all colorectal and endometrial cancer cases, and suboptimal management of Lynch syndrome in the Middle East resulted in the underdiagnosis of mutation carriers. Probands from 24 unrelated Iranian families with a history of cancer(s) suggestive of Lynch syndrome underwent microsatellite instability analysis or immunohistochemistry, multigene panel testing, copy number variation detection, or multiplex ligation-dependent probe amplification. Pathogenic variants were identified in five patients (21%), including three in MSH2, one in MSH6, and one in PMS2. Microsatellite instability analysis showed the lengths of the CAT25 marker in tumor and normal samples were 149 and 148 bp, respectively. Among 21 family members with Lynch syndrome in the MSH2 gene, identified from the three families who previously underwent cascade screening, colorectal and endometrial cancers were the most frequent. While 66% of patients had insurance that included coverage for mutation carrier screening, only one insurance provider extended coverage for next-generation sequencing. Special attention to probands and telematic management of at-risk relatives to organize blood sample collection at their convenience enhanced cascade testing 20-fold per proband. In conclusion, the age of onset and segregation analysis indicated that PMS1 may not be a cancer susceptibility gene, and the tumor spectrum in MSH2 pathogenic carriers is similar to Western countries. Collecting blood samples at patients' convenience is a possible strategy to reduce the cost of identifying Lynch syndrome through cascade testing. The genetic analysis of patients for inherited cancers would optimize the current management of Lynch syndrome in Iran by omitting noncarriers from surveillance programs., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

This study presents a family with nine children, two of them diagnosed with RTS2 using genetic testing. The other siblings show some of the RTS2 criteria and are suggestive of the syndrome. Such reports help physicians be more alert in dealing with cases of rare syndromes. Timely initiation of genetic counseling and testing once the first child was diagnosed with the syndrome could have prevented the birth of affected siblings by RTS2. Since RTS2 patients could have a severe clinical manifestation as osteosarcoma which probably leads to death at a young age, the importance of genetic testing is even more underlined., Competing Interests: The author(s) declare no competing interests., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Pathogenic mutations in BRCA1 are associated with an increased risk of hereditary breast, ovarian, and some other cancers; however, the clinical significance of many mutations in this gene remains unknown (Variants of Unknown Significance/VUS). Since mutations in intolerant regions of a protein lead to dysfunction and pathogenicity, identifying these regions helps to predict the clinical importance of VUSs. This study aimed to identify intolerant regions of BRCA1 and understand the possible root of this susceptibility. Intolerant regions appear to carry more pathogenic mutations than expected due to their lower tolerance to missense variations. Therefore, we hypothesized that among the BRCA1 regions, the higher the mutation density, the greater the intolerance. Thus, pathogenic mutation density and regional intolerance scores were calculated to identify BRCA1-intolerant regions. To investigate the pathogenic mechanisms of missense-intolerant regions in BRCA1 , transcription activation (TA) experiments and molecular dynamics (MD) simulations were also performed. The results showed that the RING domain, followed by the BRCT domain, has the highest density of pathogenic mutations. In the BRCT domain, a higher density of pathogenic mutations was observed in the inter-BRCT linker. Additionally, scores generated by Missense Tolerance Ratio-3D (MTR3D) and the Missense Tolerance Ratio consensus (MTRX) showed that the inter-BRCT linker is more intolerant than other regions of the BRCT domain. The MD results showed that mutations in the inter-BRCT linker led to cancer susceptibility, likely due to disruption of the interaction between BRCA1 and phosphopeptides. TA laboratory assays further supported the importance of the inter-BRCT linker.Communicated by Ramaswamy H. Sarma.

Multiple primary cancers (MPCs) are defined as the presence of more than one cancer in an individual that is not due to recurrence, metastasis, or local spread. Different factors such as copathogenic genetic mutations, environmental factors, lifestyle, and first cancer treatment increase the possible occurrence of subsequent malignancies. In recent years, the risk of MPCs has increased due to improved treatment; however, quadruple primary malignancies are still rare and require further investigation and treatment of the underlying cause. Here, we present a 64-year-old man with a 40-year history of cigarette smoking who developed quadruple primary malignancies of the epiglottis, kidney, pancreas, and lung. To investigate the possible genetic cause, we performed WES, and a variant of c.580G > A (Ala194Thr) was discovered in exon 5 of the Krebs cycle enzyme gene, fumarate hydratase (FH). This substitution was classified as VUS in Clinvar and likely pathogenic by Varsome and Franklin software. The structural analysis showed that the variation found was localized in a highly conserved alpha helix in the D2 domain near the FH hinge region (<6 Å), suggesting that enzyme activity was affected by a perturbation in protein quaternary structure. Because of the well-established role of FH mutations in renal cancer risk, it was possible that the FH mutation could have led to the development of renal cell carcinoma in this case. The biological mechanisms of MPCs suggest that subsequent primary malignancies are triggered by the combined effects of environmental factors, such as smoking and genetics., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Solaleh Aminian et al.)

BRCA1 and BRCA2 are two prominent genes that account for about 20-40% of inherited breast cancer. Mutations in these genes are often associated with clustering of especially early-onset cancers in the family. The spectrum of BRCA variants showed a significant difference between geographic regions and ethnicities. The frequency and spectrum of BRCA mutations in Iran, a country in southwest Asia, have not yet been thoroughly studied. Here, for the first time, all published and not published BRCA pathogenic variants are presented. Among 1040 high risk families (1258 cases) which were detected, 116 families were found to carry pathogenic variants in either BRCA1 or BRCA2. Altogether 89 distinct types of pathogenic variants have been detected in Iran, including 41 in BRCA1 and 48 in BRCA2. 16 out of 89 mutations had not been previously reported in Iran and are presented for the first time in this article, among which 4 mutations are novel worldwide. 20% of families had one of the seven most commonly observed mutations, including c.81-1G > C, c.66&#95;67delAG, c.4609C>T, c.1568delT, c.1961delA, in BRCA1 and: c.3751&#95;3752insA, c.8585dupT in BRCA2. Combining the data from published articles and our study which has not been published before, a comprehensive table is created as a reference for entire BRCA pathogenic variants and their frequencies in Iran., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68&#95;69del (p.Glu23Valfs), c.5030&#95;5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700&#95;3704del (p.Val1234Glnfs), c.4065&#95;4068del (p.Asn1355Lysfs), c.1504&#95;1508del (p.Leu502Alafs), c.843&#95;846del (p.Ser282Tyrfs), c.798&#95;799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808&#95;2811del (p.Ala938Profs), c.5722&#95;5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310&#95;1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771&#95;775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform., (© 2019 Wiley Periodicals, Inc.)