Submissions for variant NM_024675.4(PALB2):c.3476G>T (p.Trp1159Leu)

gnomAD frequency: 0.00001  dbSNP: rs587782050

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547300	SCV000633437	uncertain significance	Familial cancer of breast	2023-07-31	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 460996). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 1159 of the PALB2 protein (p.Trp1159Leu).
Ambry Genetics	RCV000564987	SCV000670714	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-05	criteria provided, single submitter	clinical testing	The p.W1159L variant (also known as c.3476G>T), located in coding exon 13 of the PALB2 gene, results from a G to T substitution at nucleotide position 3476. The tryptophan at codon 1159 is replaced by leucine, an amino acid with similar properties. In a homology-directed DNA repair (HDR) and PARP inhibitor sensitivity assays, this alteration was found to be functionally normal (Boonen RACM et al. Nat Commun, 2019 11;10:5296). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000564987	SCV001340455	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-20	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with leucine at codon 1159 of the PALB2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317262	SCV004021217	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3476G>T (p.Trp1159Leu) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes (gnomAD v2.1, Exomes dataset). 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.3476G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function and found no damaging effect of this variant on homologous recombination or in a PARP inhibitor sensitivity assay (e.g., Boonen_2019). The following publication was ascertained in the context of this evaluation (PMID: 31757951). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003329296	SCV004036285	uncertain significance	not provided	2023-03-21	criteria provided, single submitter	clinical testing	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; Published functional studies demonstrate: protein production, homologous recombination efficiency, and sensitivity to PARP inhibition to proliferation similar to wildtype (Boonen et al., 2019); This variant is associated with the following publications: (PMID: 24485656, 19609323, 20871615, 28152038, 31757951)
Myriad Genetics, Inc.	RCV000547300	SCV005084620	likely benign	Familial cancer of breast	2024-05-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.