ClinVar Genomic variation as it relates to human health

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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30093976, 27443514, 31481248, 26689913, 32255556, 19369211, 20871615, Matusin2023[Pre-Print], 34326862, 33471991, 25085752)

DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.149A>C, in exon 3 that results in an amino acid change, p.Lys50Thr. This sequence change has been previously described in individuals with breast cancer and no family history (PMID: 30093976), endometrial carcinoma (PMID: 27443514) and pancreatic ductal adenocarcinoma (PMID: 32255556). It has also been identified in a tumor specimen of an individual with breast/ovarian cancer, co-occurring with a variant in TP53 (PMID: 31481248). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs763598472). The p.Lys50Thr change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys50Thr substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Lys50Thr change remains unknown at this time.

This variant is considered likely benign. 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].

This missense variant replaces lysine with threonine at codon 50 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least five individuals affected with breast and/or ovarian, endometrial and pancreatic cancer (PMID: 27443514, 30093976; Color internal data) and glioblastoma multiforme (PMID: 26689913) and in a breast cancer case-control meta-analysis in 3/60466 cases and 6/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011210). This variant also has been detected in two individuals affected with breast and/or ovarian cancer with a pathogenic TP53 or BRCA1 variant (PMID: 31481248; Color internal data). This variant has been identified in 1/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Variant summary: PALB2 c.149A>C (p.Lys50Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.149A>C has been reported in the literature in an individual affected with glioblastoma multiforme (the cancer genome atlas (TGCA) cohort) (example, Lu_2015), an individual with endometrial carcinoma (example, Ring_2016), a patient with personal history of breast cancer and no family history (example, Chan_2018), and, as a germline variant in a study reporting the archival tumor and blood specimen testing of cancer patients undergoing multigene panel testing (example, Ong_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another germline pathogenic variant has been reported (TP53 c.1015G>T, p.Glu339Ter), providing supporting evidence for a benign role (Ong_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30093976, 26689913, 31481248, 27443514). ClinVar contains an entry for this variant (Variation ID: 220112). Based on the evidence outlined above, the variant was classified as likely benign.

The PALB2 p.Lys50Thr variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs763598472) as “With Uncertain Significance allele”, ClinVar (classified as likely benign by Ambry Genetics, and uncertain significance by Invitae, GeneDx, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and in control databases in 1 of 246260 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 1 of 17248 chromosomes (freq: 0.000058), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Lys50 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.