Submissions for variant NM_024675.4(PALB2):c.1810C>T (p.Leu604=)

gnomAD frequency: 0.00202  dbSNP: rs144015319

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030261	SCV000153882	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212801	SCV000211489	benign	not specified	2014-06-16	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	RCV000160816	SCV000212945	benign	Hereditary cancer-predisposing syndrome	2020-04-09	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.
Color Diagnostics, LLC DBA Color Health	RCV000160816	SCV000685904	benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679761	SCV000807080	likely benign	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679761	SCV000888357	benign	not provided	2022-09-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679761	SCV001500069	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP1, BP4, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798295	SCV002043589	likely benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212801	SCV002069440	likely benign	not specified	2022-01-04	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225298	SCV002504931	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160816	SCV002530650	likely benign	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212801	SCV005090204	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030261	SCV001193157	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	RCV001355308	SCV001550161	likely benign	Familial ovarian cancer		no assertion criteria provided	clinical testing	The PALB2 p.Leu604= variant was identified in 1 of 558 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and was not identified in 520 control chromosomes from healthy individuals (Zheng 2012). The variant was also identified in the following databases: dbSNP (ID: rs144015319) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color Genomics; as likely benign by Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, and in LOVD 3.0 (1x probably does not affect function). The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 151 of 277136 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 145 of 24032 chromosomes (freq: 0.01), Latino in 5 of 34418 chromosomes (freq: 0.0002), European in 1 of 126630 chromosomes (freq: 0.00001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu604= 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, 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.