ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate no damaging effect: homology-directed repair, BRCA2 interaction, and nuclear localization similar to wildtype (Rodrigue 2019, Wiltshire 2019); Observed in individuals with personal or family history of breast cancer (Nguyen-Dumont 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 31586400, 25575445, 28873162, 31636395)

This missense variant replaces isoleucine with threonine at codon 1093 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). A functional study reported this variant protein to be normal in homology-mediated DNA repair, RAD51 foci formation, BRCA2 binding, survival to PARP inhibitor olaparib treatment, and subcellular localization (PMID: 31586400, 31636395). This variant has been reported in one individual in a breast cancer family registry (PMID: 25575445), an individual affected with unspecified advanced cancer (PMID: 28873162), and an unaffected control from a breast cancer case-control study (PMID: 17200668). This variant has been identified in 2/251486 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.

In the published literature, this variant has been reported in individuals with unspecified cancers (PMIDs: 28873162 (2017) and 34326862 (2021)), as well as breast cancer (PMID: 25575445 (2015)). In addition, functional studies have shown that this variant results in normal HDR activity, PARP inhibitor olaparib sensitivity, and BRCA2 binding (PMIDs: 31586400 (2019) and 31636395 (2020)). The frequency of this variant in the general population, 0.000008 (2/251486 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1093 of the PALB2 protein (p.Ile1093Thr). This variant is present in population databases (rs45616636, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25575445, 34326862). ClinVar contains an entry for this variant (Variation ID: 182774). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400, 31636395). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.I1093T variant (also known as c.3278T>C), located in coding exon 12 of the PALB2 gene, results from a T to C substitution at nucleotide position 3278. The isoleucine at codon 1093 is replaced by threonine, an amino acid with similar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls. (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was also reported in 1/1250 probands from the Breast Cancer Family Registry (Nguyen-Dumont T et al. Breast Cancer Res. Treat. 2015 Jan;149:547-54). In one study, this alteration was identified in 0/923 familial breast cancer cases and 1/1084 controls (Rahman N et al. Nat Genet, 2007 Feb;39:165-7). In one functional study, this alteration demonstrated normal PARP inhibitor sensitivity, BRCA1/BRCA2 binding, RAD51 foci formation and homology-directed DNA repair (HDR) (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This alteration was found to be hypomorphic in another homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Found in trans with a known pathogenic variant in a woman with triple-negative breast cancer at 53 years old and previous melanoma at 44, with no signs of Fanconi Anemia.

The PALB2 p.Ile1093Thr variant was identified in 1 of 2480 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer (Nguyen Dumont 2015). The variant was also identified in dbSNP (ID: rs45616636) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color Genomics), MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic, or LOVD 3.0 databases. The variant was identified in control databases in 2 of 246268 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003), and European in 1 of 111718 chromosomes (freq: 0.00001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile1093 residue is not conserved in mammals and other organisms, and 3 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein, although this 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.