Submissions for variant NM_024675.4(PALB2):c.13C>T (p.Pro5Ser)

gnomAD frequency: 0.00004  dbSNP: rs377085677

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589509	SCV000149977	uncertain significance	not provided	2024-03-19	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, and colorectal cancer (PMID: 21285249, 24556926, 26315354, 28779002, 27616075, 29052111, 28135145, 29522266); Published functional studies demonstrate partially reduced DNA repair efficiency (PMID: 31757951); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21285249, 26315354, 27930734, 28135145, 27616075, 24556926, 29052111, 28779002, 29522266, 20871615, 19369211, Tuncer2023[CaseReport], 31757951)
Ambry Genetics	RCV000116068	SCV000185530	likely benign	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114472	SCV000290808	uncertain significance	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 5 of the PALB2 protein (p.Pro5Ser). This variant is present in population databases (rs377085677, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or ovarian cancer (PMID: 21285249, 24556926, 26315354, 27616075, 28135145, 29052111). ClinVar contains an entry for this variant (Variation ID: 126600). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 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.
Counsyl	RCV000114472	SCV000488002	uncertain significance	Familial cancer of breast	2015-12-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589509	SCV000699532	uncertain significance	not provided	2017-02-23	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.13C>T (p.Pro5Ser) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 4/118644 control chromosomes at a frequency of 0.0000337, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). This variant has been found in multiple HBOC patients without clear evidence supporting the its pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000116068	SCV000902966	likely benign	Hereditary cancer-predisposing syndrome	2015-07-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000114472	SCV001140073	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818256	SCV002072401	uncertain significance	not specified	2019-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116068	SCV002530611	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-11	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000114472	SCV002579917	uncertain significance	Familial cancer of breast	2022-05-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589509	SCV003917502	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP1, BP4, BS3:Supporting
Myriad Genetics, Inc.	RCV000114472	SCV004019730	likely benign	Familial cancer of breast	2023-04-03	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].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589509	SCV004222260	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000079 (10/126632 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast (PMID: 29052111 (2018), 28779002 (2017), 24556926 (2014), 21285249 (2011)), ovarian (PMID: 27616075 (2016), 26315354 (2015)), or colorectal cancer (PMID: 28135145 (2017)). In a large-scale breast cancer association study, the variant was reported in individuals with breast cancer as well as unaffected study controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). In addition, an experimental study on this variant’s effects on PALB2 protein function yielded inconclusive results (PMID: 31757951 (2019)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics	RCV000114472	SCV005053886	uncertain significance	Familial cancer of breast	2024-02-17	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000589509	SCV001192899	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
PreventionGenetics, part of Exact Sciences	RCV004739372	SCV005347390	uncertain significance	PALB2-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The PALB2 c.13C>T variant is predicted to result in the amino acid substitution p.Pro5Ser. This variant has been reported in four individuals with breast cancer (Casadei et al. 2011. PubMed ID: 21285249, Table S4; Myszka et al. 2018. PubMed ID: 29052111, Table 2) and an individual with ovarian cancer (Kraus et al. 2016. PubMed ID: 27616075, Table S4). The results of in vitro functional analyses for this variant were inconclusive (Boonen et al. 2019. PubMed ID: 31757951). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126600/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.