ClinVar Genomic variation as it relates to human health

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 alteration is classified as likely 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.

Variant summary: The PALB2 c.1606C>T (p.Leu536Leu) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 71/121918 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006439 (67/10406). This frequency is about 41 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications have cited the variant in affected African-American individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Taken together, this variant is classified as benign.

Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

The PALB2 p.Leu536= variant was identified in 6 of 558 proband chromosomes (frequency: 0.01075) from individuals or families with breast cancer and was present in 1 of 520 control chromosomes (frequency: 0.0019) from healthy individuals (Zheng 2012,). The variant was also identified in dbSNP (ID: rs151162255) as With other allele, ClinVar (classified as benign by GeneDX, Invitae; classified as likely benign by Ambry genetics, PALB2 database), Clinvitae (classified as benign by ClinVar), Zhejiang Colon Cancer Database (2X probably does not affect function), databases. The variant was identified in control databases in 160 of 277242 chromosomes at a frequency of 0.000577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu536= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.