ClinVar Genomic variation as it relates to human health

Variant summary: PALB2 c.315G>C (p.Glu105Asp) results in a 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 2.4e-05 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.315G>C has been reported in the literature in individuals affected with Breast Cancer (e.g., Tischkowitz_2012, Krivokuca_2019), pancreatic cancer (e.g., Mizukami_2020), and ovarian cancer (e.g., Prokofyeva_2023, Krivokuca_2019). Additionally one Japanese case-control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018); conversely, another Japanese case-control study on 1,005 pancreatic cancer patients and 23,705 controls reported the variant with an odds ratio of 7.9 (95% CI: 0.8-44.1; Mizukami_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2-associated cancers. At-least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.1054G>T, p.Glu352*) in a 46 year old with HBOC and a family history of breast cancer, providing supporting evidence for a benign role (Krivocuca_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30651582, 30287823, 22241545, 37013556, 28779002, 32980694). ClinVar contains an entry for this variant (Variation ID: 126718). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.E105D variant (also known as c.315G>C), located in coding exon 4 of the PALB2 gene, results from a G to C substitution at nucleotide position 315. The glutamic acid at codon 105 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported in multiple unique cohorts of breast and/or ovarian cancer patients, but has also been reported in healthy control populations (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80; Decker B et al. J Med Genet, 2017 11;54:732-741; Momozawa Y et al. Nat Commun. 2018 10;9:4083; Krivokuca A et al. J Hum Genet, 2019 Apr;64:281-290). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

PALB2: BP4

PM2_SUP, BP4

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 105 of the PALB2 protein (p.Glu105Asp). This variant is present in population databases (rs515726108, gnomAD 0.005%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22241545, 30287823, 30651582, 34284872). ClinVar contains an entry for this variant (Variation ID: 126718). 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 tolerated. 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.

BP1

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, one of whom also had ovarian cancer but harbored a BRCA1 pathogenic variant, pancreatic cancer, and in unaffected controls (Tischkowitz 2012, Decker 2017, Momozawa 2018, Krivokuca 2019, Mizukami 2020); This variant is associated with the following publications: (PMID: 32980694, 30651582, 28779002, 30404791, 30287823, 22241545)

This missense variant replaces glutamic acid with aspartic acid at codon 105 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 reported in 2 individuals affected with breast and/or ovarian cancer (PMID: 22241545, 30651582) and in an individual affected with childhood-onset leukemia (PMID: 31721781). This variant also has been reported in several cancer case-control studies. In two breast cancer case-control studies, this variant has been detected in 7/7051 female breast cancer cases and 5/11241 unaffected controls (PMID: 30287823) and in 4/60466 cancer cases and 1/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010032). This variant has been detected in 2/1005 pancreatic cancer cases and 6/23705 unaffected individuals (PMID: 32980694) and 2/7636 prostate cancer cases and 1/12366 unaffected individuals (PMID: 31214711). This variant has been identified in 7/282494 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.

The PALB2 c.315G>C variant is predicted to result in the amino acid substitution p.Glu105Asp. This variant was reported in individuals with breast, ovarian, pancreatic, or biliary tract cancers; however, this variant was also documented in control individuals (supplementary data 1, Momozawa et al. 2018. PubMed ID: 30287823; Table S6, Mizukami et al. 2020. PubMed ID: 32980694; Table S2, Okawa et al. 2023. PubMed ID: 36243179; Prokofyeva et al. 2023. PubMed ID: 37013556). This variant was also documented in an individual from a hereditary breast and ovarian cancer (HBOC) cohort; however, this individual also carried a nonsense BRCA1 variant (subject #ID347 in Table A.1 and Table A.2, Krivokuca et al. 2022. PubMed ID: 34284872). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126718/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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