Submissions for variant NM_024675.4(PALB2):c.1194G>A (p.Val398=)

gnomAD frequency: 0.00103  dbSNP: rs61755173

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114462	SCV000166638	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212786	SCV000170868	benign	not specified	2013-11-01	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	RCV000127307	SCV000212866	likely benign	Hereditary cancer-predisposing syndrome	2014-06-16	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	RCV000114462	SCV000268040	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000327932	SCV000396117	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000127307	SCV000396118	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127307	SCV000685859	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588666	SCV000699523	benign	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: Variant Summary: The c.1194G>A (p.Val398=) in PALB2 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.073% (88/121172 chrs tested), mainly in individuals of European descent (0.1154%; 77/66698 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic PALB2 variant (0.015%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls without personal or family history of cancer. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000588666	SCV000807069	likely benign	not provided	2017-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212786	SCV000889569	benign	not specified	2021-03-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000114462	SCV001140041	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588666	SCV001247806	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170350	SCV001332924	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000114462	SCV001429089	uncertain significance	Familial cancer of breast	2018-03-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588666	SCV001473704	likely benign	not provided	2023-08-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212786	SCV002070064	likely benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127307	SCV002530593	likely benign	Hereditary cancer-predisposing syndrome	2021-03-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212786	SCV002551681	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000127307	SCV000886695	likely benign	Hereditary cancer-predisposing syndrome	2018-11-19	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000588666	SCV001193071	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	RCV001357080	SCV001552421	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Val398= variant was identified in 10 of 7040 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Spanish, Italian, German, and Australian nationalities and was present in 9 of 6464 control chromosomes (frequency: 0.001) from healthy individuals (Blanco 2012, Catucci 2014, Hellebrand 2011, Thompson 2015). The variant was also identified in dbSNP (ID: rs61755173) as “with Likely benign, other allele”, in ClinVar and Clinvitae databases as benign by Invitae, GeneDx, PALB2 database and likely benign by Ambry Genetics, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, and Illumina Clinical Services; and identified 2X in the LOVD 3.0 database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer databases. The variant was identified in the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008) and in the NHLBI GO Exome Sequencing Project in 20 of 8600 European American African alleles. In addition, the variant was identified in control databases in 212 of 276616 chromosomes at a frequency of 0.0008 in the following populations: African in 9 of 24030 chromosomes (freq. 0.0004), Latino in 19 of 34416 chromosomes (freq. 0.0006), European Non-Finnish in 170 of 126264 chromosomes (freq. 0.001), Ashkenazi Jewish in 9 of 10148 chromosomes (freq. 0.0009), European Finnish in 1 of 25660 chromosomes (freq. 0.00004), and Other in 4 of 6454 chromosomes (freq. 0.0006) but was not seen in East Asian and South Asian POP populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Val398= 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 addition, 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588666	SCV001741104	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588666	SCV001797532	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212786	SCV001807038	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588666	SCV001905847	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000588666	SCV001927879	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588666	SCV001955958	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588666	SCV001964845	likely benign	not provided		no assertion criteria provided	clinical testing