Submissions for variant NM_024675.4(PALB2):c.2442G>A (p.Glu814=)

gnomAD frequency: 0.00005  dbSNP: rs140776736

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212812	SCV000211491	benign	not specified	2014-08-08	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	RCV000160818	SCV000213532	likely benign	Hereditary cancer-predisposing syndrome	2014-06-27	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.
Invitae	RCV001030308	SCV000253593	likely benign	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160818	SCV000537509	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212812	SCV000699567	likely benign	not specified	2021-01-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590716	SCV000888370	likely benign	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212812	SCV002551662	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492441	SCV004239557	likely benign	Breast and/or ovarian cancer	2023-01-29	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030308	SCV001193228	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	RCV001354891	SCV001549610	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Glu814= variant was identified in 1 of 194 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer (Ding 2011). The variant was also identified in dbSNP (ID: rs140776736) as “With Likely benign allele”, in ClinVar (classified as benign by GeneDx; as liklely benign by Ambry Genetics, Invitae, Color genomics; as uncertain significance by two clinical laboratories), Clinvitae, and LOVD 3.0 (as does not affect function). The variant was not identified in Cosmic, or the Zhejiang University Database. The variant was identified in control databases in 12 of 277244 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24038 chromosomes (freq: 0.00004), Latino in 1 of 34420 chromosomes (freq: 0.00003), and European in 10 of 126724 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu814= 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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.