Submissions for variant NM_024675.4(PALB2):c.3251C>T (p.Ser1084Leu)

gnomAD frequency: 0.00009  dbSNP: rs62625271

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656940	SCV000211530	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	Published functional studies are conflicting: decreased homologous recombination and reduced nuclear localization; BRCA1 interaction and cell survival after exposure to olaparib similar to wild type (PMID: 31586400, 32048105); Observed in several individuals with breast or ovarian cancer, but has also been seen in multiple unaffected controls (PMID: 17200668, 23824750, 26315354, 28779002, 29522266, 30287823, 32048105, 36243179); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28279176, 28779002, 23824750, 17200668, 26315354, 29522266, 30287823, 32048105, 31586400, 24485656, 19609323, 20871615, 36243179)
Ambry Genetics	RCV000160852	SCV000215057	likely benign	Hereditary cancer-predisposing syndrome	2021-01-04	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.
Eurofins Ntd Llc (ga)	RCV000656940	SCV000225703	uncertain significance	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114610	SCV000255100	uncertain significance	Familial cancer of breast	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1084 of the PALB2 protein (p.Ser1084Leu). This variant is present in population databases (rs62625271, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 23824750, 26315354, 32048105, 35263119). ClinVar contains an entry for this variant (Variation ID: 126727). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400, 32048105). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000114610	SCV000489200	uncertain significance	Familial cancer of breast	2016-09-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656940	SCV000601778	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing	The PALB2 c.3251C>T (p.Ser1084Leu) variant has been reported in the published literature in individuals with breast cancer (PMID: 32885271 (2021), 30287823 (2018), 29522266 (2018), 28779002 (2017), 23824750 (2014)) and ovarian cancer (PMID: 23824750 (2021)). This variant has also been observed in unaffected individuals (PMID: 31214711 (2020), 26315354 (2015), 17200668 (2007)). A functional study has demonstrated neutral effects of this variant on BRCA2-protein interaction and cell survival based on DNA damage response (PMID: 31586400 (2019)). However, another study showed this variant caused a loss of PALB2 nuclear localization and recruitment of the RAD51 protein involved in DNA damage repair (PMID: 32048105 (2020)). The frequency of this variant in the general population, 0.00019 (25/129170 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000764043	SCV000894997	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	RCV000160852	SCV000910827	likely benign	Hereditary cancer-predisposing syndrome	2016-02-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001116749	SCV001274878	uncertain significance	Fanconi anemia complementation group N	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656940	SCV002010961	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114610	SCV004019649	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493439	SCV004242679	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003493439	SCV004803879	uncertain significance	not specified	2025-02-27	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3251C>T (p.Ser1084Leu) 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 9.1e-05 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Fanconi Anemia Type N (9.1e-05 vs 0.00028), allowing no conclusion about variant significance. c c.3251C>T has been reported in the literature in non-cancer control individuals (e.g. Momozawa_2018, Kaemer_2019, Rahman_2010, Ramus_2015) and also in individuals affected with breast cancer (including triple-negative breast cancer), epithelial ovarian cancer or tubo-ovarian cancer, without evidence for causality (e.g. Wong-Brown_2014, Ramus_2015, Toh_2020, Delahunty_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Type N. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in vitro in a PARP2-inhibitor sensitivity assay or yeast-two hybrid assay (e.g. Rodrigue_2019). The following publications have been ascertained in the context of this evaluation (PMID: 35263119, 31422574, 30287823, 17200668, 26315354, 31586400, 32048105, 23824750). ClinVar contains an entry for this variant (Variation ID: 126727). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656940	SCV005411273	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	BS1
PreventionGenetics, part of Exact Sciences	RCV004739377	SCV000807105	uncertain significance	PALB2-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The PALB2 c.3251C>T variant is predicted to result in the amino acid substitution p.Ser1084Leu. This variant has been documented in individuals with triple negative breast and ovarian cancers, but was also identified in an unaffected control cohort (Wong-Brown et al. 2014. PubMed ID: 23824750; Ramus et al. 2015, Table S4. PubMed ID: 26315354; Kluska et al. 2017. PubMed ID: 28279176). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126727/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV000656940	SCV001193376	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358132	SCV001553792	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ser1084Leu variant was identified in 4 of 9012 proband chromosomes (frequency: 0.0004) from individuals or families with breast or ovarian cancer and in 3 of 9030 (frequency: 0.0003) control chromosomes (Wong-Brown 2014, Rahman 2007, Ramus 2015). The variant was also identified in the following databases: dbSNP (ID: rs62625271) as “With Uncertain significance allele”, ClinVar and Clinvitae (6x classified as uncertain significance by GeneDx, Ambry Genetics, EGL Genetic Diagnostics, Invitae, Counsyl and in the PALB2 database), and the LOVD 3.0 database (reported 3x classified as effect unknown or not classified). The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 25 of 277214 chromosomes (no homozygotes) at a frequency of 0.00009 in the following populations: European non-Finnish in 23 of 126714 chromosomes (freq. 0.0002); Ashkenazi Jewish in 2 of 10152 chromosomes (freq. 0.0002) increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ser1084Leu residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.