Submissions for variant NM_024675.4(PALB2):c.1010T>C (p.Leu337Ser)

gnomAD frequency: 0.01508  dbSNP: rs45494092

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114450	SCV000153863	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121752	SCV000170867	benign	not specified	2013-09-11	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	RCV000127306	SCV000212728	benign	Hereditary cancer-predisposing syndrome	2014-11-18	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.
Vantari Genetics	RCV000127306	SCV000267068	benign	Hereditary cancer-predisposing syndrome	2015-12-03	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114450	SCV000267994	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000127306	SCV000292108	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000121752	SCV000297318	benign	not specified	2015-07-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121752	SCV000314369	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000127306	SCV000396119	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000114450	SCV000488406	benign	Familial cancer of breast	2016-03-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000127306	SCV000576467	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755592	SCV000604599	benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001116860	SCV001274994	benign	Fanconi anemia complementation group N	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798291	SCV002043580	benign	Breast and/or ovarian cancer	2020-01-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127306	SCV002530577	benign	Hereditary cancer-predisposing syndrome	2021-05-12	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000755592	SCV002545769	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BS1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121752	SCV002551683	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114450	SCV004044116	benign	Familial cancer of breast	2023-05-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ITMI	RCV000121752	SCV000085950	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114450	SCV000207347	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000127306	SCV000788083	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000755592	SCV001193052	benign	not provided	2019-08-07	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354445	SCV001549062	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu337Ser variant was identified in 190 of 11072 proband chromosomes (frequency: 0.0175) from individuals or families with CMM, breast, ovarian cancer, and was present in 98 of 6466 control chromosomes (frequency: 0.015) from healthy individuals (Aoude 2014, Catucci 2014, Garcia 2009, Nguyen-Dumont 2013, Tischkowitz 2012, Teo 2013, Prokofyeva 2012, Wong-Brown 2014, Zheng 2012). The variant was also identified in dbSNP (ID: rs45494092) as “With other allele,” ClinVar (classified as benign by Ambry Genetics, Vantari Genetics, Color Genomics, DGDCHP, PreventionGenetics, Counsyl, Invitae, GeneDx, Pathway Genomics; classified as likely benign by Illumina; classified as uncertain significance by CGLPMCC, PALB2 database), Clinvitae (classified with conflicting interpretations of pathogenicity by ClinVar), LOVD 3.0, databases. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 42189 (43 homozygous) of 276766 chromosomes at a frequency of 0.01524 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu337 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000121752	SCV001743446	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000755592	SCV001799563	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000755592	SCV001809269	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121752	SCV001906158	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000755592	SCV001927278	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121752	SCV001953663	benign	not specified		no assertion criteria provided	clinical testing