Submissions for variant NM_024675.4(PALB2):c.23C>T (p.Pro8Leu)

gnomAD frequency: 0.00051  dbSNP: rs150390726

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589826	SCV000211560	likely benign	not provided	2020-12-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate moderate PARPi sensitivity, moderate interaction with BRCA1, cellular localization similar to wild type, normal response to DNA damage, reduced RAD51 foci formation, and normal or decreased HDR activity (Rodrigue 2019, Wiltshire 2019); 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: 32185139, 33169439, 32209438, 31636395, 31658756, 31586400, 23555315, 25503501, 28944238, 28528518, 26315354, 25186627, 21113654)
Ambry Genetics	RCV000160872	SCV000217148	likely benign	Hereditary cancer-predisposing syndrome	2020-05-12	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	RCV000114527	SCV000262327	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589826	SCV000699564	likely benign	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The c.23C>T (p.Pro8Leu) in PALB2 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is located in the a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.0001801 (20/ 111058 chrs tested), predominantly in individuals of African descent (0.001817; 16/ 8808 chrs tested). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.000156, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pt without strong evidence for causality. The variant is cited as VUS/Likely Benign by reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as Likely Benign.
Color Diagnostics, LLC DBA Color Health	RCV000160872	SCV000910788	likely benign	Hereditary cancer-predisposing syndrome	2016-01-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589826	SCV001134544	likely benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000589826	SCV001140072	benign	not provided	2022-12-13	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225301	SCV002504952	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160872	SCV002530695	likely benign	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004529922	SCV004115008	uncertain significance	PALB2-related disorder	2022-11-11	criteria provided, single submitter	clinical testing	The PALB2 c.23C>T variant is predicted to result in the amino acid substitution p.Pro8Leu. This variant has been reported in individuals with breast and colorectal cancer; however, a causative association has not been established (Ding et al. 2011. PubMed ID: 21113654; Tung et al. 2014. PubMed ID: 25186627, Supplemental Table 2; Maxwell et al. 2014. PubMed ID: 25503501, Supplemental Table 1; Cock-Rada et al. 2018. PubMed ID: 28528518, Table 2; DeRycke et al. 2017. PubMed ID: 28944238, Supplemental Table S2). Functional studies of this variant are conflicting, with some indicating similar function to wild type protein (Rodrigue et al. 2019. PubMed ID: 31586400). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23652456-G-A). ClinVar classifications range from likely benign to uncertain, with a consensus of recent classifications pointing toward likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126652/). Although we suspect this alteration is more likely benign, at this time, the clinical significance of this variant is uncertain due to insufficient functional and genetic evidence.
Leiden Open Variation Database	RCV000589826	SCV001192901	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.