{"id":4391,"date":"2025-12-18T17:00:27","date_gmt":"2025-12-18T17:00:27","guid":{"rendered":"http:\/\/sebigec.es\/blog\/?guid=64ba7d965c846adebf41e0f13e887d09"},"modified":"2026-02-20T12:16:58","modified_gmt":"2026-02-20T12:16:58","slug":"evidence-for-pathogenicity-of-brca2-c-8351ga-p-arg2784gln-and-the-challenges-in-classification-of-pathogenic-variants-with-reduced-penetrance","status":"publish","type":"post","link":"https:\/\/sebigec.es\/blog\/index.php\/2025\/12\/18\/evidence-for-pathogenicity-of-brca2-c-8351ga-p-arg2784gln-and-the-challenges-in-classification-of-pathogenic-variants-with-reduced-penetrance\/","title":{"rendered":"Evidence for pathogenicity of BRCA2 c.8351G&gt;A p.(Arg2784Gln) and the challenges in classification of pathogenic variants with reduced penetrance"},"content":{"rendered":"\n<sec><st>Background<\/st>\n<p>The <I>BRCA2<\/I> c.8351G&gt;A p.(Arg2784Gln) variant has long been classified as a variant of uncertain significance (VUS) due to conflicting evidence used in variant classification. This study aims to clarify its pathogenicity and associated risks for breast and ovarian cancer.<\/p>\n<\/sec>\n<sec><st>Methods<\/st>\n<p>This study was conducted by the international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium. We collected data from 29 informative families with this variant. Co-segregation likelihood ratios (LRs) were calculated using the full-likelihood method to assess pathogenicity, and cancer risks were estimated with modified segregation analysis.<\/p>\n<\/sec>\n<sec><st>Results<\/st>\n<p>Co-segregation analysis using a grid search across scaled penetrance levels for <I>BRCA2<\/I> truncating variants yielded the strongest evidence in favour of pathogenicity, with LR maximised at approximately 20% of full penetrance (LR=11.026). Furthermore, estimated breast cancer risks were markedly higher for early onset breast cancer; women diagnosed at &lt;50 years had a HR of 4.5, compared with a HR of 1.65 for women diagnosed at &ge;50 years. The estimated lifetime risks were 25% for breast cancer and 6% for ovarian cancer.<\/p>\n<p>Evidence of pathogenicity was also supported by the presence of the variant allele in two patients with Fanconi anaemia.<\/p>\n<\/sec>\n<sec><st>Conclusions<\/st>\n<p>Our results indicate that <I>BRCA2<\/I> c.8351G&gt;A p.(Arg2784Gln) has a disease-causing effect, with reduced penetrance, similar to other pathogenic variants in moderate risk breast cancer genes such as <I>ATM<\/I> and <I>CHEK2<\/I>. We also provide risk-adapted recommendations for clinical management. Importantly, one should be aware of a reduced penetrance as the underlying reason for conflicting results among pieces of evidence used for variant classification.<\/p>\n<\/sec>\n","protected":false},"excerpt":{"rendered":"<p>Background<br \/>\nThe BRCA2 c.8351G&gt;A p.(Arg2784Gln) variant has long been classified as a variant of uncertain significance (VUS) due to conflicting evidence used in variant classification. This study aims to clarify its pathogenicity and associated risk&#8230;<\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,14],"tags":[83],"class_list":["post-4391","post","type-post","status-publish","format-standard","hentry","category-articulos","category-jmg","tag-jmedgenet"],"_links":{"self":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4391","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/comments?post=4391"}],"version-history":[{"count":2,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4391\/revisions"}],"predecessor-version":[{"id":9968,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/posts\/4391\/revisions\/9968"}],"wp:attachment":[{"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/media?parent=4391"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/categories?post=4391"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sebigec.es\/blog\/index.php\/wp-json\/wp\/v2\/tags?post=4391"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}