Submissions for variant NM_024675.4(PALB2):c.53A>G (p.Lys18Arg)

gnomAD frequency: 0.00530  dbSNP: rs138789658

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121743	SCV000170863	benign	not specified	2014-01-15	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	RCV000129207	SCV000183956	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114647	SCV000261906	benign	Familial cancer of breast	2025-02-04	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114647	SCV000267978	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000129207	SCV000292124	benign	Hereditary cancer-predisposing syndrome	2015-01-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000376271	SCV000396135	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	RCV000129207	SCV000396136	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000440737	SCV000511038	benign	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121743	SCV000596217	benign	not specified	2019-07-14	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129207	SCV000679741	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121743	SCV000807114	benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121743	SCV000859745	likely benign	not specified	2018-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000440737	SCV001473088	benign	not provided	2020-04-27	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225309	SCV002504950	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129207	SCV002531203	benign	Hereditary cancer-predisposing syndrome	2020-07-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121743	SCV002551695	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000440737	SCV004143338	likely benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	PALB2: BS1
ITMI	RCV000121743	SCV000085941	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114647	SCV000207346	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000440737	SCV001192913	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000440737	SCV001554409	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Lys18Arg variant was identified in 20 of 8974 proband chromosomes (frequency: 0.002) from German, Russian, French, (African) American and Australian individuals or families with breast cancer (BRCA1/2 negative or familial or early onset) and early onset prostate cancer, and was identified in 2 of 6682 chromosomes from healthy individuals (frequency: 0.0003) (Bogdanova_2011_21165770, Damiola_2015_26564480, Ding_2011_21113654 , Nguyen_Dumont_2015, Thompson_2015_26283626, Zheng_2012_21932393, Tischkowitz_2008_18288683, Bodian_2014_24728327). The variant was found in 1 proband with prostate cancer as well as his unaffected brother (Tischkowitz_2008_18288683). Functional analysis of PALB2 interaction with BRCA1 showed the variant did not significantly affect complex formation, while partially impairing HR (homologous recombination) DNA repair activity of PALB2 (Foo_2017_ 28319063). The variant was also identified in dbSNP (ID: rs138789658) “With other allele”, ClinVar (classified with conflicting interpretations of pathogencity; submitters: benign by GeneDx, Ambry Genetics, Invitae, Color Genomics, Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics) and Pathway Genomics; likely benign by PALB2 database, Genetic Services Laboratory (University of Chicago), Illumina; uncertain significance by Cancer Genetics Laboratoy (Peter MacCallum Cancer Center), and classification not provided by ITMI), Clinvitae (5x), LOVD 3.0 (1x), Zhejiang Colon Cancer Database (1x) and was not identified in MutDB. The variant was identified in control databases in 489 (3 homozygous) of 277224 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 440 (3 homozygous) of 24030 chromosomes (freq: 0.02), Other in 4 of 6464 chromosomes (freq: 0.0006), Latino in 32 of 34420 chromosomes (freq: 0.0009), European Non-Finnish in 12 of 126714 chromosomes (freq: 0.0001), East Asian in 1 of 18868 chromosomes (freq: 0.00005); it was not observed in the Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Lys18 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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	RCV000121743	SCV001807661	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121743	SCV001905874	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121743	SCV001958436	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000121743	SCV002034129	benign	not specified		no assertion criteria provided	clinical testing