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	2024-11-04	criteria provided, single submitter	clinical testing	Observed in individuals with PALB2-related and other cancers, but also in healthy controls (PMID: 20582465, 25356972, 26564480, 26315354, 26283626, 25980754, 28779002, 29522266, 32546565, 35264596, 36605468); Published functional studies suggest no damaging effect: PARP inhibitor sensitivity and BRCA1 interaction comparable to wild type (PMID: 31586400); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20582465, 24728327, 25356972, 26283626, 26564480, 25980754, 28779002, 26315354, 29522266, 33471991, 32546565, 20871615, 19369211, 35264596, 36605468, 31586400, 34326862)
Ambry Genetics	RCV000116075	SCV000185541	likely benign	Hereditary cancer-predisposing syndrome	2024-04-03	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	RCV000168167	SCV000218828	uncertain significance	Familial cancer of breast	2025-01-29	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 (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 128124). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". 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	2024-05-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585283	SCV000692847	likely benign	not provided	2024-05-01	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
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	2025-02-27	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). These results showed no damaging effect of this variant. ClinVar contains an entry for this variant (Variation ID: 128124). 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	2025-03-04	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
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168167	SCV005402235	uncertain significance	Familial cancer of breast	2024-03-26	criteria provided, single submitter	clinical testing	The PALB2 c.194C>T (p.Pro65Leu) missense change has a maximum subpopulation frequency of 0.009% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, and a functional study supports that this variant does not substantially impact protein function (PMID: 31586400). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
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