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Peer reviewed: True, Funder: UK Medical Research Council PhD pro-gramme, Simple Summary: As the treatment for breast cancer continues to improve and more women survive their initial diagnosis, there is an increasingly large number of women who are at risk of a second new breast cancer in their lifetimes. However, the hereditary causes of these second breast cancers are not well understood. In this study, we used the latest genetic sequencing technologies to investigate hereditary causes for the second breast cancer in individuals who are known not to have alterations in one of the three main breast cancer genes (BRCA1, BRCA2 and PALB2). We analyzed the genetic profiles of selected participants from the WECARE study, one of the largest studies looking at second breast cancers in women. By comparing the genetic profiles of women who have had one breast cancer to similarly matched women who went on to have a second breast cancer, we found that younger women (under 50) with second breast cancers had a higher number of inherited gene alterations compared with those women with one breast cancer. We did not see the same effect in the older women. The results from this study improve our understanding of the hereditary contribution to second breast cancers. Abstract: Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. Methods: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC). Results: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2–5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7–2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1). Conclusion: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.