Submissions for variant NM_024675.4(PALB2):c.1285A>G (p.Ile429Val)

dbSNP: rs1555461360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803604	SCV000943483	uncertain significance	Familial cancer of breast	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 429 of the PALB2 protein (p.Ile429Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 648799). 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. 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.
Ambry Genetics	RCV001010753	SCV001170992	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-20	criteria provided, single submitter	clinical testing	The p.I429V variant (also known as c.1285A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1285. The isoleucine at codon 429 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/1781 patients referred for BRCA1/2 gene testing and 0/377 with significant personal and family history who had previously tested negative for BRCA1/2 mutations, and the study authors classified p.I429V as a low risk variant of unknown significance (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly 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	RCV001759532	SCV002006588	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV001010753	SCV002530600	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Color Diagnostics, LLC DBA Color Health	RCV001010753	SCV004357933	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 429 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Leiden Open Variation Database	RCV000803604	SCV001193086	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.