Submissions for variant NM_024675.4(PALB2):c.3495G>A (p.Ser1165=)

gnomAD frequency: 0.00121  dbSNP: rs45439097

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082966	SCV000166664	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212828	SCV000170864	benign	not specified	2013-12-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000127303	SCV000212903	likely benign	Hereditary cancer-predisposing syndrome	2014-06-15	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.
PreventionGenetics, part of Exact Sciences	RCV000212828	SCV000314378	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384114	SCV000396072	likely benign	Fanconi anemia complementation group N	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000127303	SCV000396073	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127303	SCV000686046	benign	Hereditary cancer-predisposing syndrome	2015-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586081	SCV000699599	benign	not provided	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The c.3495G>A variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however, it may strengthen a cryptic 5' splicing donor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 89/125390 control chromosomes at a frequency of 0.0007098, which is about 5 times of the maximal expected frequency of a pathogenic allele (0.0001563), suggesting this variant is benign. In addition, mutliple clinical laboratories/reputable databases/literatures classified this variant as benign/polymorphism. Taken together, this variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586081	SCV000888377	benign	not provided	2022-06-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586081	SCV001150860	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586081	SCV001159009	benign	not provided	2019-09-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798301	SCV002043604	likely benign	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212828	SCV002070042	benign	not specified	2021-05-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127303	SCV002531186	likely benign	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001082966	SCV002548551	likely benign	Familial cancer of breast	2022-05-15	criteria provided, single submitter	clinical testing	PALB2:c.3495G>A is present in 0.070% in the large population studies (GnomAd). The deep exonic variant is predicted to create a de novo donor splice site in the last exon (exon 13) of PALB2 by in silico splicing tools. Functional RNA study has shown that the variant does not cause splicing aberration (PMID: 35806449). Therefore the variant was classified as likely benign (ACMG/AMP: BS3-Stand alone, BS1, PP3).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212828	SCV002551623	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000586081	SCV001193417	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355544	SCV001550463	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000384114	SCV001552758	likely benign	Fanconi anemia complementation group N		no assertion criteria provided	clinical testing	The PALB2 p.Ser1165Ser variant was identified in 19 of 8732 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 11 of 4896 control chromosomes (frequency: 0.002) from healthy individuals (Papi_2010_19763884, Ding_2011_20927582, Bogdanova_2011_21165770, Hellebrand_2011_21618343, Nguyen-Dumont_2013_24206657, Thompson_2015_26283626, Aoude_2014_24949998, Zhen_2015_25356972). The variant was also identified in dbSNP (ID: rs45439097) as “With other allele”, ClinVar (2x as benign by GeneDx, Invitae, 5x as likely benign by Ambry Genetics, Prevention Genetics, Illumina Clinical services, Quest Diagnostics, PALB2 database), Clinvitae (4x, as benign and likely benign by ClinVar), LOVD 3.0 (6x reported) and Zhejiang Colon Cancer Database (1x. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 192 of 277176 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 29 of 24016 chromosomes (freq: 0.0012), other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 11 of 34420 chromosomes (freq: 0.0003), European Non-Finnish in 149 of 126698 chromosomes (freq: 0.0012), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition the variant was identified by our laboratory in 1 individual with breast and skin cancer with a co-occurring pathogenic BRCA2 variant (c.8904delC p.Val2969CysfsX7), increasing the likelihood that the p.Ser1165Ser variant does not have clinical significance. The p.Ser1165Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586081	SCV001809030	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000586081	SCV001906178	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000586081	SCV001929933	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586081	SCV001953542	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586081	SCV002037908	likely benign	not provided		no assertion criteria provided	clinical testing