Submissions for variant NM_024675.4(PALB2):c.2418G>A (p.Pro806=)

gnomAD frequency: 0.00002  dbSNP: rs577076372

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162786	SCV000213264	likely benign	Hereditary cancer-predisposing syndrome	2014-11-29	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	RCV000233118	SCV000290836	likely benign	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001721029	SCV000518164	likely benign	not provided	2018-10-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26564480)
Color Diagnostics, LLC DBA Color Health	RCV000162786	SCV000685949	likely benign	Hereditary cancer-predisposing syndrome	2016-02-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426070	SCV001361354	likely benign	not specified	2019-02-22	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2418G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.3e-05 in 300258 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.00017 (in the gnomAD database and from publication data: Damiola 2015, Momozawa 2018). The observed variant frequency within East Asian control individuals is higher than the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (HBOC) (0.00016), strongly suggesting that the variant is a benign polymorphism. Though the variant c.2418G>A has been reported in the literature in individuals affected with breast cancer (Catucci 2014, Momozawa 2018), it was also found in several healthy controls (Damiola 2015, Momozawa 2018). The authors of a large case-control association study, involving unselected breast cancer (BrC) patients and controls of Japanese ancestry, concluded that the variant is benign (Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000162786	SCV002530697	likely benign	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Leiden Open Variation Database	RCV000426070	SCV001193226	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.