Submissions for variant NM_024675.4(PALB2):c.844A>G (p.Arg282Gly)

gnomAD frequency: 0.00001  dbSNP: rs45447991

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220267	SCV000274951	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.R282G variant (also known as c.844A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 844. The arginine at codon 282 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in multiple studies in breast and/or ovarian patients as well as unaffected control subjects (Rahman N et al. Nat. Genet., 2007 Feb;39:165-7; Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is poorly 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	RCV000462094	SCV000550805	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 282 of the PALB2 protein (p.Arg282Gly). This variant is present in population databases (rs45447991, gnomAD 0.003%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 231184). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759905	SCV000889596	uncertain significance	not provided	2018-04-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220267	SCV000911106	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 282 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). 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 been reported in an individual affected with ovarian cancer in the literature. This variant has been identified in 2/251410 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.
Sema4, Sema4	RCV000220267	SCV002531230	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	curation
GeneDx	RCV000759905	SCV002540407	uncertain significance	not provided	2023-09-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Ramus et al., 2015; Decker et al., 2017; Dorling et al., 2021; Rahman et al., 2007); This variant is associated with the following publications: (PMID: 28779002, 26315354, 30287823, 19369211, 33471991, 36243179, 17200668)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491976	SCV004239567	uncertain significance	Breast and/or ovarian cancer	2022-11-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000462094	SCV005053929	uncertain significance	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000759905	SCV001193029	uncertain significance	not provided	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.