Submissions for variant NM_024675.4(PALB2):c.2607C>T (p.Ser869=)

dbSNP: rs45542234

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123340	SCV000166656	benign	Familial cancer of breast	2025-02-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000212814	SCV000170857	benign	not specified	2013-11-06	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	RCV000127296	SCV000213294	likely benign	Hereditary cancer-predisposing syndrome	2014-06-20	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	RCV000123340	SCV000488047	likely benign	Familial cancer of breast	2015-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127296	SCV000685963	benign	Hereditary cancer-predisposing syndrome	2015-10-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587582	SCV000699571	benign	not provided	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.2607C>T (p.Ser869Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. This variant was found in 68/121400 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.005766 (60/10406). This frequency is about 37 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000212814	SCV002065061	likely benign	not specified	2019-08-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127296	SCV002530710	benign	Hereditary cancer-predisposing syndrome	2020-12-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212814	SCV002551653	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587582	SCV003800296	benign	not provided	2022-03-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149845	SCV003838083	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123340	SCV004019627	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.
CeGaT Center for Human Genetics Tuebingen	RCV000587582	SCV005894285	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV004528843	SCV000314373	benign	PALB2-related disorder	2020-03-10	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Leiden Open Variation Database	RCV000212814	SCV001193263	benign	not specified	2018-08-25	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587582	SCV001553246	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Ser869= variant was identified in 1 of 1846 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and was not identified in 2168 control chromosomes from healthy individuals (Rahman 2007). The variant was also identified in the following databases: dbSNP (ID: rs45542234) as "With Likely benign, other allele", ClinVar (2x benign, 3x likely benign), and Clinvitae. The variant was not identified in Cosmic, MutDB, LOVD 3.0, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 154 of 277240 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 138 of 24036 chromosomes (freq: 0.006), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 4 of 34420 chromosomes (freq: 0.0001), and South Asian in 9 of 30782 chromosomes (freq: 0.0003). The variant was not observed in the European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Ser869= 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. One of five 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587582	SCV001977620	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587582	SCV001977676	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587582	SCV001979699	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587582	SCV002034153	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212814	SCV002036891	benign	not specified		no assertion criteria provided	clinical testing