ClinVar Genomic variation as it relates to human health

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

PALB2: BS1, BS2

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The PALB2 p.Lys18Arg variant was identified in 20 of 8974 proband chromosomes (frequency: 0.002) from German, Russian, French, (African) American and Australian individuals or families with breast cancer (BRCA1/2 negative or familial or early onset) and early onset prostate cancer, and was identified in 2 of 6682 chromosomes from healthy individuals (frequency: 0.0003) (Bogdanova_2011_21165770, Damiola_2015_26564480, Ding_2011_21113654 , Nguyen_Dumont_2015, Thompson_2015_26283626, Zheng_2012_21932393, Tischkowitz_2008_18288683, Bodian_2014_24728327). The variant was found in 1 proband with prostate cancer as well as his unaffected brother (Tischkowitz_2008_18288683). Functional analysis of PALB2 interaction with BRCA1 showed the variant did not significantly affect complex formation, while partially impairing HR (homologous recombination) DNA repair activity of PALB2 (Foo_2017_ 28319063). The variant was also identified in dbSNP (ID: rs138789658) “With other allele”, ClinVar (classified with conflicting interpretations of pathogencity; submitters: benign by GeneDx, Ambry Genetics, Invitae, Color Genomics, Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics) and Pathway Genomics; likely benign by PALB2 database, Genetic Services Laboratory (University of Chicago), Illumina; uncertain significance by Cancer Genetics Laboratoy (Peter MacCallum Cancer Center), and classification not provided by ITMI), Clinvitae (5x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x) and was not identified in MutDB. The variant was identified in control databases in 489 (3 homozygous) of 277224 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 440 (3 homozygous) of 24030 chromosomes (freq: 0.02), Other in 4 of 6464 chromosomes (freq: 0.0006), Latino in 32 of 34420 chromosomes (freq: 0.0009), European Non-Finnish in 12 of 126714 chromosomes (freq: 0.0001), East Asian in 1 of 18868 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Lys18 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.