Submissions for variant NM_024675.4(PALB2):c.2608G>A (p.Val870Ile)

gnomAD frequency: 0.00004  dbSNP: rs376641234

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132122	SCV000187190	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-27	criteria provided, single submitter	clinical testing	The p.V870I variant (also known as c.2608G>A), located in coding exon 7 of the PALB2 gene, results from a G to A substitution at nucleotide position 2608. The valine at codon 870 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000656937	SCV000211519	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28419882, 26315354, 29263802, 24485656, 19609323, 20871615, 33471991, 33298767, 28873162)
Invitae	RCV000227189	SCV000290843	uncertain significance	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 870 of the PALB2 protein (p.Val870Ile). This variant is present in population databases (rs376641234, gnomAD 0.05%). This missense change has been observed in individual(s) with ovarian, colorectal or an unspecified advanced cancer (PMID: 26315354, 28873162, 33298767). ClinVar contains an entry for this variant (Variation ID: 142746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000227189	SCV000487914	uncertain significance	Familial cancer of breast	2015-12-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212815	SCV000596221	uncertain significance	not specified	2017-02-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132122	SCV000902885	likely benign	Hereditary cancer-predisposing syndrome	2015-07-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000227189	SCV001140000	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212815	SCV001737774	uncertain significance	not specified	2021-06-05	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2608G>A (p.Val870Ile) results in a conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2608G>A has been reported in the literature in individuals with serous/colorectal cancer undergoing multigene panel testing (example Ramus_2015, Marks_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000132122	SCV002530711	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000227189	SCV004019651	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Baylor Genetics	RCV000227189	SCV004202166	uncertain significance	Familial cancer of breast	2023-07-18	criteria provided, single submitter	clinical testing