Submissions for variant NM_024675.4(PALB2):c.3428T>A (p.Leu1143His)

gnomAD frequency: 0.00006  dbSNP: rs62625284

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585950	SCV000150013	uncertain significance	not provided	2023-07-19	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 demonstrate minimal to no impact on protein abundance and activity (Boonen et al., 2019); This variant is associated with the following publications: (PMID: 33558524, 24448499, 24556926, 26343384, 25186627, 26898890, 26689913, 31422574, 22692731, 20852946, 26283626, 25479140, 26564480, 27067391, 26315354, 27099641, 27878467, 21618343, 29522266, 30455982, 31512090, 34426522, 33630411, 33471991, 33980423, 32658311, 30306255, 33195396, 31451522, 35264596, 31206626, 28944238, 28779002, 20871615, 19609323, 24485656, 36672847, 36605468, 31757951)
Invitae	RCV000114625	SCV000166662	likely benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116104	SCV000186860	likely benign	Hereditary cancer-predisposing syndrome	2018-12-18	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114625	SCV000268028	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114625	SCV000487859	uncertain significance	Familial cancer of breast	2015-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804169	SCV000699596	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3428T>A (p.Leu1143His) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251470 control chromosomes, predominantly at a frequency of 0.00027 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin.c.3428T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Balia_2010, Damiola_2015, Ramus_2015, Thompson_2015, Bonache_2018, Scarpitta_2019, Weitzel_2019, Akcay_2021, Dorling_2021, Moradian_2021, Solmaz_2021) but it was also detected in unaffected controls (e.g. Akcay_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (SDHB c.269G>A, p.Arg90Gln; MLH1 c.676C>T, p.Arg226X; Ferrer-Avargues_2021, Moradian_2021). Experimental evidence evaluating an impact on protein function demonstrated the variant had 70% homologous recombination efficiency compared to wild-type and similar relative resistance to PARPi with wild-type (Boonen_2020). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=12) and benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004528795	SCV000807109	uncertain significance	PALB2-related disorder	2023-05-23	criteria provided, single submitter	clinical testing	The PALB2 c.3428T>A variant is predicted to result in the amino acid substitution p.Leu1143His. This variant has been reported in patients with breast and/or ovarian cancer (Catucci et al. 2012. PubMed ID: 22692731; Balia et al. 2010. PubMed ID: 20852946; Moradian et al. 2021. PubMed ID: 33558524; Scarpitta et al. 2019. PubMed ID: 31512090; Hellebrand et al. 2011. PubMed ID: 21618343). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23614913-A-T), and it is listed in ClinVar with conflicting interpretations of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126740/). Functional studies have been inconclusive on the impact of this variant on protein function (Park et al. 2014. PubMed ID: 24141787; Boonen et al. 2019. PubMed ID: 31757951). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics	RCV000116104	SCV000838993	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585950	SCV000888376	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer, as well as in healthy control individuals (PMIDs: 20852946 (2010), 22692731 (2012), 24556926 (2014), 25186627 (2015), 26283626 (2015), 26315354 (2015), 26564480 (2015), 26898890 (2016), 27878467 (2016), 28779002 (2017), 31512090 (2019), 33558524 (2021), 33980423 (2021), 34478935 (2021)). A functional study using mammalian cells indicated this variant caused a reduction in DNA repair activity, but not resistance to cisplatin, a DNA cross linking agent (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.0016 (18/11610 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764041	SCV000894995	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116104	SCV000902660	likely benign	Hereditary cancer-predisposing syndrome	2016-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585950	SCV001747152	uncertain significance	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001804169	SCV002067128	uncertain significance	not specified	2021-03-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3428T>A, in exon 13 that results in an amino acid change, p.Leu1143His. This sequence change has been described in gnomAD with a low population frequency of 0.016% (dbSNP rs62625284). The p.Leu1143His change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is \ known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu1143His substitution. This sequence change has been observed in multiple individuals with breast, ovarian, or pancreatic cancer, but has also been observed in normal controls (PMID: 27878467; 25479140; 26315354; 26283626; 21618343). Another variant affecting the same codon, p.Leu1143Pro has been reported in an individual with bilateral breast cancer. Functional studies demonstrated that the p.Leu143Pro disrupted the PALB2-RAD51C-BRCA2 complex indicating the functional importance of the Leu1143 residue (PMID:24141787, PMID:21618343). Due to the lack of sufficient evidences, the clinical significance of the p.Leu1143His change remains unknown at this time
Sema4, Sema4	RCV000116104	SCV002531178	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114625	SCV004019613	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. 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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001804169	SCV004027057	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000585950	SCV005197069	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001004833	SCV000987257	uncertain significance	bilateral breast cancer	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria This variant is in exon 8 of the PALB2 gene, which is involved in repairing double-strand DNA breaks in WD40 repeat-like (V872- 1185 aa) domain, which serves as platforms for the assembly of protein complexes (e.g., BRCA1 / RAD51) or mediators of transient interplay among other proteins. This variant is in a hotspot of 12 pathogenic nonsense and frameshift variants, including one mutation (i.e., c.3426dupA; p.Leu1143Thrfs) at the same position (Source ClinVar) (PM1 Pathogenic Moderate). It has been reported in several cancers including breast cancers (PMID: 27878467; 25479140; 26315354; 26283626; 21618343). Furthermore, it has been experimentally shown that this missense change modestly reduces DNA double-stranded break-induced homologous recombination, affects the PALB2 protein interaction with RAD51C, XRCC3 and BRCA2 proteins and moderately increases cellular sensitivity to ionizing radiation (PMID: 24141787). 6 pathogenic predictions from EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from DANN, DEOGEN2, MVP, PrimateAI and REVEL support its deleterious effect (PP3 Pathogenic Supporting). This variant was found in a 46-years old female with bilateral breast cancer and no reported family history of cancer. In summary, the available evidence is currently insufficient to determine the role of this variant in the disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585950	SCV001979714	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000585950	SCV001980565	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000585950	SCV002035732	uncertain significance	not provided		no assertion criteria provided	clinical testing