Submissions for variant NM_024675.4(PALB2):c.1250C>A (p.Ser417Tyr)

gnomAD frequency: 0.00011  dbSNP: rs45510998

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590540	SCV000149974	uncertain significance	not provided	2024-09-12	criteria provided, single submitter	clinical testing	Observed in several individuals with PALB2-related and other cancers, but also in healthy controls (PMID: 17200668, 22241545, 26315354, 25186627, 25980754, 28779002, 29458332, 33471991, 34204722); Reported in a multiethnic exome array study, but no statistically significant association with breast cancer was identified after correcting for multiple comparisons (PMID: 23555315); Published functional studies are inconclusive: partial reduction of ChAM-mediated chromatin association and reduced interaction with nucleosome core particles, but homology directed repair activity comparable to wild-type (PMID: 22193777, 31757951, 32041954, 31636395); 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: 25980754, 26315354, 22241545, 17200668, 26283626, 29458332, 28779002, 27930734, 25186627, 29387807, 31636395, 32255556, 32041954, 31757951, 35264596, 34357101, 26467025, 26976419, 33471991, 34204722, 23555315, 22193777, 38175342, 36922933, 25085752)
Ambry Genetics	RCV000116065	SCV000186632	likely benign	Hereditary cancer-predisposing syndrome	2021-05-20	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	RCV000114466	SCV000218549	likely benign	Familial cancer of breast	2025-01-29	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114466	SCV000267998	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114466	SCV000489329	uncertain significance	Familial cancer of breast	2016-09-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116065	SCV000537539	likely benign	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255214	SCV000699527	likely benign	not specified	2024-09-23	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1250C>A (p.Ser417Tyr) results in a non-conservative amino acid change in 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 0.00012 in 256854 control chromosomes, predominantly at a frequency of 0.00023 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 1.5 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.1250C>A has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with breast cancer, colorectal cancer, and pancreatic ductal adenocarcinoma (e.g., Tischkowitz_2012, Yurgelun_2015, Cremin_2020, Fonfria_2021). However, 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 (e.g., PMS2 c.2095G>C, p.D699H; SMAD4 c.1447+2T>C), providing supporting evidence for a benign role (Huelsman_2021, Henn_2019). In homology directed repair (HDR) assays, the variant was found to have either slightly reduced or normal activity (e.g., Boonen_2019, Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 29387807, 31757951, 32255556, 29458332, 34204722, 30680046, 34357101, 17200668, 26283626, 22241545, 31636395, 25980754). ClinVar contains an entry for this variant (Variation ID: 126595). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000116065	SCV000839041	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590540	SCV001134533	benign	not provided	2022-07-11	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590540	SCV002010983	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001255214	SCV002067217	uncertain significance	not specified	2018-06-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116065	SCV002530596	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000114466	SCV002556675	uncertain significance	Familial cancer of breast	2022-01-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116065	SCV002819244	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114466	SCV004019723	benign	Familial cancer of breast	2023-04-03	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]. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001255214	SCV004027086	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BS1, BP1
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483472	SCV004228275	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-19	criteria provided, single submitter	curation	Missense variant with relative high AF (0.000205773) in NFE. According to the ClinGen ACMG PALB2 v1.0.0 criteria we chose these criteria: BP1 (supporting benign): Based on published and unpublished functional studies, PALB2 has a low rate of missense variants that are non-functional in relevant assays. True missense pathogenic variants are not yet confirmed or refuted but are thought to be exceedingly rare. Given the very low likelihood that missense variants are pathogenic, this rule applies to all missense variants in PALB2., BS1 (strong benign): popmax:NFE popmax AF:0.000205773
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394371	SCV006057719	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2021-10-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590540	SCV006077687	likely benign	not provided	2025-04-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV004739371	SCV000807071	uncertain significance	PALB2-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The PALB2 c.1250C>A variant is predicted to result in the amino acid substitution p.Ser417Tyr. This variant has been reported in individuals with pancreatic ductal adenocarcinoma (PDAC, Supp. Table 3, Cremin et al. 2020. PubMed ID: 32255556) and breast cancer (Guindalini et al. 2022. PubMed ID: 35264596; Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991), in individuals undergoing Lynch Syndrome testing (Supplemental Table 2, Yurgelun et al. 2015. PubMed ID: 25980754), and has also been observed in healthy control cohorts (Rahman et al. 2006. PubMed ID: 17200668; Breast Cancer Association Consortium et al 2021. PubMed ID: 33471991). In vitro experiments suggest the p.Ser417Tyr amino acid change does not drastically reduce homology directed repair (HDR) activity of PALB2 (Wiltshire et al. 2019. PubMed ID: 31636395; Boonen et al. 2019. PubMed ID: 31757951), while another functional study showed that this variant reduced PALB2 chromatin association, and partially destabilized the PALB2 protein (Bleuyard et al. 2017. PubMed ID: 29387807). This variant is reported in 0.023% 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 a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126595/). 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	RCV000590540	SCV001193082	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.