ClinVar

Description

The PALB2 p.Glu1018Asp variant was identified in 6 of 3322 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Kim 2016, Li 2015, Nakagomi 2016, Phuah 2013, Thompson 2015). The variant was also identified in the following databases: dbSNP (ID: rs183489969) as With Likely benign, Uncertain significance, other allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, CGLPMCC; classified as likely benign by Illumina; classified as Benign by Invitae), Clinvitae (conflicting interpretations of pathogenicity), Cosmic (none (score 0.69)), MutDB , LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 102 of 277208 chromosomes at a frequency of 0.000368 in the following populations: other in 3 of 6464 chromosomes (freq. 0.00046), European in 1 of 126704 chromosomes (freq. 0.000008), East Asian in 98 of 18868 chromosomes (freq. 0.005), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Glu1018 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the WD40-repeat-containing domain. The variant p.Glu1018Asp was listed as a rare missense variant in a study of 155 Japanese patients with breast and/or ovarian cancers; in this family, the family history of 25 relatives was available but none were reported with breast and/or ovarian cancer (Nakagomi 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.