Submissions for variant NM_024675.4(PALB2):c.1419A>C (p.Pro473=)

gnomAD frequency: 0.00309  dbSNP: rs62625275

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212794	SCV000170870	benign	not specified	2013-12-16	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	RCV000127309	SCV000212819	likely benign	Hereditary cancer-predisposing syndrome	2014-06-18	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	RCV000114473	SCV000261726	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000114473	SCV000487912	likely benign	Familial cancer of breast	2015-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212794	SCV000596215	likely benign	not specified	2016-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127309	SCV000685877	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585974	SCV000699533	benign	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.1419A>C (p.Pro473Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing and alteration to an ESE binding site, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 129/121282 (1/939, 2 homozygotes), predominantly in the African cohort, 121/10362 (1/85, 2 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PALB2 variant of 1/6397. Therefore, suggesting the variant is a common polymorphism found in population(s) of African origin. In addition, multiple reputable clinical laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into considearation, the variant of interest has been classified as Benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000127309	SCV000747821	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212794	SCV000807075	benign	not specified	2017-06-20	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225294	SCV002504938	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212794	SCV002551678	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585974	SCV002822295	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BP7, BS1, BS2
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315610	SCV004016496	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114473	SCV004019729	benign	Familial cancer of breast	2023-04-03	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492438	SCV004239547	benign	Breast and/or ovarian cancer	2022-12-19	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000127309	SCV000805275	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000114473	SCV001193100	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	RCV001358133	SCV001553793	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Pro473= variant was identified in 4 of 3246 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and was not identified in 2082 control chromosomes from healthy individuals (Damiola 2015, Ding 2011, Hellebrand 2011, Sauty de Chalon 2010). The variant was also identified in the following databases: dbSNP (ID: rs62625275), ClinVar (classified as benign by GeneDx, Invitae, Color Genomics, Laboratory Corporation of America; as likely benign by Ambry Genetics, Counsyl, GSLUOC, PALB2 database), Clinvitae (conflicting interpretations of pathogenicity), Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 270 of 276902 chromosomes (2 homozygous) 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 242 of 24034 chromosomes (freq: 0.01), “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 21 of 34414 chromosomes (freq: 0.001), European in 4 of 126400 chromosomes (freq: 0.00003), and South Asian in 2 of 30782 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Pro473= 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 this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212794	SCV001800038	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212794	SCV001906330	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212794	SCV001926624	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585974	SCV001957996	likely benign	not provided		no assertion criteria provided	clinical testing