Submissions for variant NM_024675.4(PALB2):c.620C>G (p.Pro207Arg)

dbSNP: rs515726125

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114649	SCV000260710	uncertain significance	Familial cancer of breast	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 207 of the PALB2 protein (p.Pro207Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 22052327). ClinVar contains an entry for this variant (Variation ID: 126760). 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). 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	RCV000776330	SCV000911675	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces proline with arginine at codon 207 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 a family affected with breast and/or ovarian cancer (PMID: 22052327) and in an unaffected control individual in a breast cancer case-control study (PMID: 33471991). This variant has been identified in 1/251410 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.
Ambry Genetics	RCV000776330	SCV001187120	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-07	criteria provided, single submitter	clinical testing	The p.P207R variant (also known as c.620C>G), located in coding exon 4 of the PALB2 gene, results from a C to G substitution at nucleotide position 620. The proline at codon 207 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in 1/131 BRCA1/2 negative individuals with a personal and/or family history suggestive of hereditary breast cancer, including at least one case of male breast cancer (Blanco A et al. Breast Cancer Res. Treat., 2012 Feb;132:307-15). This alteration was also reported in 0/60,466 breast cancer cases and in 1/53,461 controls in another study (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a BRCA1 binding assay, this alteration was found to have intermediate activity (Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). 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.
GeneDx	RCV001572249	SCV001796857	uncertain significance	not provided	2021-03-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate BRCA2 interaction and PARP inhibitor response to be comparable to wild type (Rodrigue 2019); Observed in an individual with a personal or family history of breast cancer (Blanco 2012); This variant is associated with the following publications: (PMID: 31586400, 22052327, 33195396)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001572249	SCV004222352	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with personal and/or family history of breast and/or ovarian cancer, including male breast cancer (PMID: 22052327 (2012)). An experimental study reports this variant does not significantly affect PALB2 protein function, however further studies are needed to determine an overall impact (PMID: 31586400 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV000114649	SCV001192993	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.