PALB2 NM_024675.3:c.2027T>C, Ile676Thr

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

Variant summary: The PALB2 c.2027T>C (p.Ile676Thr) variant causes a missense change involving a non-conserved nucleotide with 4/5 in silico tools predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 85/128258 (1/1428), predominantly in the Latino cohort, 85/11578 (1/136), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PALB2 variant of 1/6397. Therefore, suggesting the variant is a common polymorphism found in population(s) of Latino origin. The variant of interest has been reported in affected individuals via publications. Clinical diagnostic laboratories have cited the variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign.