Submissions for variant NM_024675.4(PALB2):c.587G>A (p.Arg196Lys)

gnomAD frequency: 0.00001  dbSNP: rs730881904

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160865	SCV000211549	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Shindo et al., 2017); This variant is associated with the following publications: (PMID: 32659497, 20871615, 19369211, 28767289)
Ambry Genetics	RCV000216462	SCV000278731	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-03	criteria provided, single submitter	clinical testing	The p.R196K variant (also known as c.587G>A), located in coding exon 4 of the PALB2 gene, results from a G to A substitution at nucleotide position 587. The arginine at codon 196 is replaced by lysine, an amino acid with highly similar properties. This alteration was identified in multiple cohorts of individuals diagnosed with pancreatic cancer or other periampullary neoplasms tested for hereditary cancer risk via multi-gene panels (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14). This alteration was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228567	SCV000290886	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 196 of the PALB2 protein (p.Arg196Lys). This variant is present in population databases (rs730881904, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28767289, 32659497). ClinVar contains an entry for this variant (Variation ID: 182785). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000216462	SCV000690940	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 196 of the PALB2 protein. Computational prediction tool 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 individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011157). This variant has been identified in 2/251414 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160865	SCV001470586	uncertain significance	not provided	2020-08-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535049	SCV004113154	uncertain significance	PALB2-related disorder	2023-03-17	criteria provided, single submitter	clinical testing	The PALB2 c.587G>A variant is predicted to result in the amino acid substitution p.Arg196Lys. This variant has been reported with uncertain significance, in the heterozygous state, in an individual with pancreatic ductal adenocarcinoma and with a family history of prostate cancer (Patient Case ID Case_5*16, Table A2, Shindo et al. 2017. PubMed ID: 28767289). The c.587G>A variant was also reported with uncertain significance in a study of individuals with pancreatic ductal adenocarcinoma (eAppendix, Supplementary Table 2, Hu et al. 2020. PubMed ID: 32659497). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23647280-C-T) and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182785/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV000228567	SCV004189524	likely benign	Familial cancer of breast	2023-11-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].