Submissions for variant NM_024675.4(PALB2):c.909C>T (p.Leu303=)

gnomAD frequency: 0.00101  dbSNP: rs145788619

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212781	SCV000170865	benign	not specified	2013-11-23	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	RCV000127304	SCV000212828	likely benign	Hereditary cancer-predisposing syndrome	2014-08-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114670	SCV000252867	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212781	SCV000314379	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000127304	SCV000396124	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000300127	SCV000396125	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.
Counsyl	RCV000114670	SCV000488221	likely benign	Familial cancer of breast	2016-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127304	SCV000686081	likely benign	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531848	SCV001747153	likely benign	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212781	SCV002069350	likely benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127304	SCV002531234	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114670	SCV004019644	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001531848	SCV004563615	benign	not provided	2023-11-14	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114670	SCV001193038	likely 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	RCV001358321	SCV001554021	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu303= variant was identified in 2 of 5770 proband chromosomes (frequency: 0.0003) from individuals or families with prostate or breast cancer and was not identified in 520 control chromosomes from healthy individuals (Tischkowitz 2008, Zheng 2012). The variant was also identified in dbSNP (ID: rs145788619) as "With other allele", ClinVar (classified as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, Counsyl, Color Genomics and one other clinical laboratory), and in LOVD 3.0 database (2x). The variant was not identified in Cosmic, MutDB, or the Zhejiang University database. The variant was identified in control databases in 96 of 277112 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 86 of 24026 chromosomes (freq: 0.004), Latino in 9 of 34418 chromosomes (freq: 0.0003), and European in 1 of 126634 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu303= 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) do not predict a difference in splicing. 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	RCV000212781	SCV002035291	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001531848	SCV002036796	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001531848	SCV002037465	likely benign	not provided		no assertion criteria provided	clinical testing