Submissions for variant NM_024675.4(PALB2):c.2469C>G (p.Leu823=)

dbSNP: rs515726087

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205616	SCV000261300	likely benign	Familial cancer of breast	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000440482	SCV000518068	likely benign	not specified	2017-07-02	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	RCV000570985	SCV000663293	likely benign	Hereditary cancer-predisposing syndrome	2015-08-05	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.
Counsyl	RCV000205616	SCV000786189	likely benign	Familial cancer of breast	2018-03-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570985	SCV000911676	likely benign	Hereditary cancer-predisposing syndrome	2017-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440482	SCV000919941	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570985	SCV002530699	likely benign	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000205616	SCV004019187	benign	Familial cancer of breast	2023-03-30	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355858	SCV001550864	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Leu823= variant (c.2469C>A, an alternate substitution) was identified in 1 of 1494 proband chromosomes (frequency: 0.0007) from Australian individuals or families with BRCA1/2 negative breast cancer (Teo 2013). The variant was also identified in ClinVar (classified likely benign by Invitae, GeneDx and Ambry Genetics) and Clinvitae (2x); and was not identified in dbSNP, Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Leu823= 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.
PreventionGenetics, part of Exact Sciences	RCV004530233	SCV004709934	likely benign	PALB2-related disorder	2023-05-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).