Submissions for variant NM_024675.4(PALB2):c.194C>T (p.Pro65Leu)

gnomAD frequency: 0.00004  dbSNP: rs62625272

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585283	SCV000149984	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: PARP inhibitor sensitivity and BRCA1 interaction comparable to wild type (Rodrigue et al., 2019); Observed in individuals with PALB2-related and other cancers, but also in healthy controls (Adank et al., 2011; Zhen et al., 2015; Damiola et al., 2015; Ramus et al., 2015; Thompson et al., 2015; Yurgelun et al., 2015; Decker et al., 2017; Hauke et al., 2018; Song et al., 2021; Guindalini et al., 2022; Subaolu et al., 2023); This variant is associated with the following publications: (PMID: 20582465, 24728327, 25356972, 26283626, 26564480, 25980754, 28779002, 26315354, 29522266, 31586400, 33471991, 32546565, 20871615, 19369211, 35264596, 36605468)
Ambry Genetics	RCV000116075	SCV000185541	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The p.P65L variant (also known as c.194C>T), located in coding exon 3 of the PALB2 gene, results from a C to T substitution at nucleotide position 194. The proline at codon 65 is replaced by leucine, an amino acid with similar properties. This alteration has been detected in multiple cancer cohorts as well as healthy controls (Adank MA et al. Breast Cancer Res. Treat. 2011 Jun;127:357-62; Damiola F et al. Breast Cancer Res. Treat. 2015 Dec;154:463-71; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Song H et al. J Med Genet, 2021 05;58:305-313). Additionally, in a BRCA1/BRCA2 binding assay, this alteration was found to have normal activity (Rodrigue A et al. Nucleic Acids Res, 2019 11;47:10662-10677). 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.
Invitae	RCV000168167	SCV000218828	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 65 of the PALB2 protein (p.Pro65Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast, ovarian, and/or pancreatic cancer (PMID: 20582465, 25356972, 26315354, 26564480, 35264596). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 128124). 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 leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000168167	SCV000267980	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585283	SCV000601746	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000093 (12/129184 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in families with breast, ovarian or pancreatic cancer (PMID: 20582465 (2011)), individuals with breast cancer (PMID: 28779002 (2017), 26564480 (2015), 35264596 (2022)), ovarian cancer (PMID: 26315354 (2015), 32546565 (2021)), pancreatic cancer (PMID: 25356972 (2015)), Lynch syndrome (PMID: 25980754 (2015)) and in unaffected controls (PMID: 28779002 (2017), 26283626 (2015)). In a large scale breast cancer association study, the variant was found in both breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). Functional studies found that this variant performed similar to wild type and showed normal function in a PARP inhibitor assay (PMID: 31586400 (2019)), and also showed little functional impact in BRCA2 binding and recruitment kinetics assays (PMID: 33139182 (2021)). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000585283	SCV000692847	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Counsyl	RCV000168167	SCV000785932	uncertain significance	Familial cancer of breast	2018-01-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000116075	SCV000839057	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116075	SCV000902796	likely benign	Hereditary cancer-predisposing syndrome	2015-07-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000168167	SCV001140065	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121745	SCV001983662	likely benign	not specified	2023-09-07	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.194C>T (p.Pro65Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251470 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. However, the variant was observed in the North-western European subpopulation with an even higher allele frequency, 0.00017 (i.e. 7/42220 alleles), and this frequency is similar to the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting that the variant might be a benign polymorphism. The variant, c.194C>T, has been reported in the literature in individuals affected with breast cancer and other tumor phenotypes, however it was also reported in several healthy controls (e.g. Adank_2011, Bodian_2014, Zhen_2015, Yurgelun_2015, Thompson_2015, Ramus_2015, Damiola_2015, Decker_2017, Hauke_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. However, in a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 12/60466 cases, but was also found in 11/53461 controls, suggesting no increased relative risk for breast cancer development (Dorling_2021 through LOVD). In addition, at least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had BRCA1-binding similar to wild-type, and had normal function in a drug sensitivity (PARP inhibitor) assay (Rodrigue_2019). The following publications have been ascertained in the context of this evaluation (PMID: 20582465, 24728327, 26564480, 33471991, 29522266, 33139182, 26315354, 31586400, 26283626, 25980754, 25356972, 35264596, 28779002). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and VUS (n=11). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121745	SCV002551692	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000168167	SCV004019655	likely benign	Familial cancer of breast	2023-03-31	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].
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000168167	SCV004177262	uncertain significance	Familial cancer of breast		criteria provided, single submitter	not provided
ITMI	RCV000121745	SCV000085943	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV001030125	SCV001192938	uncertain significance	Pancreatic cancer, susceptibility to, 3	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000585283	SCV001798451	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000585283	SCV001930932	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585283	SCV001955103	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000585283	SCV002035207	likely benign	not provided		no assertion criteria provided	clinical testing