Submissions for variant NM_024675.4(PALB2):c.925A>G (p.Ile309Val)

gnomAD frequency: 0.00919  dbSNP: rs3809683

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114672	SCV000153932	benign	Familial cancer of breast	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000121749	SCV000170866	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	RCV000129841	SCV000184657	benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000114672	SCV000267993	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000129841	SCV000396122	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000335364	SCV000396123	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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129841	SCV000679739	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129841	SCV000686082	benign	Hereditary cancer-predisposing syndrome	2014-12-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121749	SCV000807118	benign	not specified	2017-04-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757594	SCV000885884	benign	not provided	2022-12-28	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225312	SCV002504940	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121749	SCV002551684	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315625	SCV004016501	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000757594	SCV005213526	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000121749	SCV000085947	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000129841	SCV000788097	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000757594	SCV001193041	benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357007	SCV001552329	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ile309Val variant was identified in 41 of 4986 proband chromosomes (frequency: 0.008) from individuals or families with breast Cancer of African-American, Chinese, Malaysian and Singaporean descent and was present in 50 of 4390 control chromosomes (frequency: 0.011) from healthy individuals (Ding 2011, Li 2015, Phuah 2013, Wong-Brown 2014, Zheng 2012, Sluiter 2009). The variant was also identified in dbSNP (ID: rs3809683) as “Other”, ClinVar (benign by GeneDx, Ambry Genetics, Invitae), PALB2 Database (likely benign by Cancer Genetics Laboratory and Illumina Clinical Services Laboratory), LOVD 3.0 (8x with no classification) Zhejiang Colon Cancer Database (1x as unknown). The variant was not identified in Cosmic, MutDB, databases. The variant was further identified in the 1000 Genomes Project in 58 of 5000 chromosomes (freq. 0.01) and the NHLBI GO Exome Sequencing Project in 126 of 4394 African American alleles (freq. 0.03). The variant was identified in control databases in 932 of 277056 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Notably the variant was identified in the African population in 690 of 24026 chromosomes (freq. 0.02) including 10 homozygous individuals. The p.Ile309 residue is not conserved in mammals and the variant amino acid (Val) is present in Macaca mulatta, Rattus norvegicus, and Mus musculus increasing the likelihood that this variant does not have clinical significance. In addition, 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, this variant is classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121749	SCV001799549	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121749	SCV001807953	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121749	SCV001906093	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121749	SCV001954530	benign	not specified		no assertion criteria provided	clinical testing