Submissions for variant NM_024675.4(PALB2):c.629C>T (p.Pro210Leu)

gnomAD frequency: 0.02101  dbSNP: rs57605939

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114650	SCV000153883	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131969	SCV000187027	benign	Hereditary cancer-predisposing syndrome	2014-11-19	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.
Eurofins Ntd Llc (ga)	RCV000121750	SCV000230431	benign	not specified	2015-01-07	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000131969	SCV000267069	likely benign	Hereditary cancer-predisposing syndrome	2016-02-04	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114650	SCV000267989	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000131969	SCV000292123	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000131969	SCV000396130	benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000306267	SCV000396131	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131969	SCV000576429	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121750	SCV000807115	benign	not specified	2014-03-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705820	SCV001474618	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001705820	SCV001832747	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798303	SCV002043607	benign	Breast and/or ovarian cancer	2019-10-11	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225310	SCV002504942	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121750	SCV002551689	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000121750	SCV000085948	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114650	SCV000207349	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000114650	SCV001192994	benign	Familial cancer of breast	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	RCV001358034	SCV001553671	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Pro210Leu variant was identified in 65 of 10554 proband chromosomes (frequency: 0.006) from individuals or families with breast cancer and was present in 37 of 8955 control chromosomes (frequency: 0.0005) from healthy individuals (Rahman_2007_17200668, Garcia_2009_18302019, Ding_2011_21113654, Zheng_2012_21932393, Tischkowitz_2012_22241545, Thompson_2015_26283626). The variant was also identified in the following databases: dbSNP (ID: rs57605939) as “With other allele”, ClinVar (8x, as benign by Invitae, Ambry, EGL Genetic, Color Genomics, Illumina, Pathway Genomics, PALB2 database, 2x as likely benign, by Cancer Genetics, Institute for Biomarker, 1x as uncertain significant by ITMI), Clinvitae (3x as benign and 3x with conflicting interpretations of pathogenicity by ClinVar and EmvClass), LOVD 3.0 (5x). The variant was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1750 of 277182 chromosomes (51 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1618 of 24022 chromosomes (freq: 0.07), other in 13 of 6468 chromosomes (freq: 0.002), Latino in 105 of 34420 chromosomes (freq: 0.003), European Non-Finnish in 10 of 126682 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 10152 chromosomes (freq: 0.0001), and South Asian in 3 of 30782 chromosomes (freq: 0.0001), while the variant was not observed in the East Asian, European Finnish, populations. The p.Pro210Leu residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121750	SCV001808853	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121750	SCV001905892	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121750	SCV001959283	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000121750	SCV002035533	benign	not specified		no assertion criteria provided	clinical testing