ClinVar Genomic variation as it relates to human health

Variant summary: PALB2 c.1766C>T (p.Thr589Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250874 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1766C>T in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This missense variant replaces threonine with methionine at codon 589 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 a breast cancer case-control meta-analysis in 3/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010342), and it also has been reported in an individual affected with colorectal cancer (PMID: 28944238). This variant has been identified in 6/282278 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.

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.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer (DeRycke et al., 2017); This variant is associated with the following publications: (PMID: 28944238, 33471991)

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 589 of the PALB2 protein (p.Thr589Met). This variant is present in population databases (rs773340677, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 187669). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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.

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

The PALB2 p.Thr589Met variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs773340677) as “With Uncertain significance allele”, in ClinVar and Clinvitae (4x as uncertain significance by Ambry Genetics, Invitae, GeneDx, Color Genomics) and LOVD 3.0 (1x). The variant was identified in control databases in 6 of 276658 chromosomes at a frequency of 0.000022 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34408 chromosomes (freq: 0.00003), European Non-Finnish in 4 of 126266 chromosomes (freq: 0.00003), East Asian in 1 of 18858 chromosomes (freq: 0.00005); it was not observed in the African, Other, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr589Met residue is not 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 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.

The PALB2 c.1766C>T variant is predicted to result in the amino acid substitution p.Thr589Met. This variant has been reported in individuals with breast cancer (supplemental data, Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991) and in a case of mismatch repair deficient colorectal cancer (Table S2, DeRycke et al. 2017. PubMed ID: 28944238). However, it has also been reported in a control cohort in a study of biliary tract cancer (Table S2, Okawa et al. 2023. PubMed ID: 36243179). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/187669/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.