Submissions for variant NM_024675.4(PALB2):c.3539T>C (p.Ile1180Thr)

gnomAD frequency: 0.00001  dbSNP: rs180177139

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479423	SCV000568195	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20180015, 31586400, 31757951, 31636395, 30613976, 24485656, 19609323, 20871615, 33606809, 32830346)
Ambry Genetics	RCV000569135	SCV000663364	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-24	criteria provided, single submitter	clinical testing	The p.I1180T variant (also known as c.3539T>C), located in coding exon 13 of the PALB2 gene, results from a T to C substitution at nucleotide position 3539. The isoleucine at codon 1180 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in cohorts of individuals diagnosed with breast cancer, male breast cancer and kidney cancer (Silvestri V et al. Breast Cancer Res. Treat., 2010 Jul;122:299-301; Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363; Smith PS et al. Genes Chromosomes Cancer, 2021 01;60:5-16). This alteration was found to be functionally inconclusive in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). In another study, this alteration was found to be functionally normal by a homology-directed DNA repair (HDR) assay and a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114633	SCV000814107	uncertain significance	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1180 of the PALB2 protein (p.Ile1180Thr). This variant is present in population databases (rs180177139, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 20180015, 33606809). ClinVar contains an entry for this variant (Variation ID: 126747). 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, 31757951). 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.
Color Diagnostics, LLC DBA Color Health	RCV000569135	SCV000908454	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824604	SCV002074415	uncertain significance	not specified	2022-01-23	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3539T>C (p.Ile1180Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 251458 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3539T>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with male breast cancer/breast cancer (example, Silvestri_2010, Sandoval_2021, Rizzolo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/PALB2-related disorders. Multiple publications report experimental evidence evaluating an impact on protein function (example, Boonen_2019, Wiltshire_2020). The most pronounced variant effect results in high homologous recombination activity ascertained at levels ranging from 70-80% of wild-type depending upon the study. Five 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000479423	SCV004222347	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer, male breast cancer, and kidney cancer (PMIDs: 20180015 (2010), 30613976 (2019), 33606809 (2021), and 32830346 (2021)). Studies have shown that this variant has no significant effect on PALB2 function using an HDR assay or PARP inhibitor sensitivity assay (PMIDs: 31757951 (2019), 31586400 (2019), and 31636395 (2020)). The frequency of this variant in the general population, 0.000004 (1/251458 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV000114633	SCV005055039	uncertain significance	Familial cancer of breast	2023-11-21	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114633	SCV001193425	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
PreventionGenetics, part of Exact Sciences	RCV004739380	SCV005360699	uncertain significance	PALB2-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The PALB2 c.3539T>C variant is predicted to result in the amino acid substitution p.Ile1180Thr. This variant was reported in individuals with breast cancer (Table 1, Silvestri et al. 2010. PubMed ID: 20180015; Table S4, Sandoval et al. 2021. PubMed ID: 33606809) including males with breast cancer (Table 1, Silvestri et al. 2010. PubMed ID: 20180015; Supplementary Table 3, Rizzolo et al. 2019. PubMed ID: 30613976). Experimental studies have shown that this missense change does not have a significant effect on PALB2 function (Table S3 and Supplemental Figures S2 and S3, Rodrigue et al. 2019. PubMed ID: 31586400; Figures 2, 3A and 4A, Boonen et al. 2019. PubMed ID: 31757951). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126747/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.