Submissions for variant NM_024675.4(PALB2):c.1316G>T (p.Gly439Val)

gnomAD frequency: 0.00004  dbSNP: rs537258442

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167944	SCV000218592	uncertain significance	Familial cancer of breast	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 439 of the PALB2 protein (p.Gly439Val). This variant is present in population databases (rs537258442, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188096). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive 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.
GeneDx	RCV000588409	SCV000567882	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with retinoblastoma (PMID: 26580448); This variant is associated with the following publications: (PMID: 26580448, 33471991, 22193777)
Ambry Genetics	RCV000565232	SCV000670614	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	The p.G439V variant (also known as c.1316G>T), located in coding exon 4 of the PALB2 gene, results from a G to T substitution at nucleotide position 1316. The glycine at codon 439 is replaced by valine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole-exome sequencing; this patient was diagnosed with retinoblastoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000565232	SCV000685870	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 439 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 detected in a breast cancer case-control meta-analysis in 0/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010728). This variant has been identified in 3/281264 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818401	SCV000699529	uncertain significance	not specified	2023-04-07	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1316G>T (p.Gly439Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249874 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1316G>T has been reported in the literature in an individual affected with retinoblastoma (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000167944	SCV000784838	uncertain significance	Familial cancer of breast	2017-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765276	SCV000896529	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818401	SCV002069622	uncertain significance	not specified	2020-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565232	SCV002530602	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588409	SCV002774674	uncertain significance	not provided	2022-10-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000011 (3/281264 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a large breast cancer association study in an unaffected individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PALB2). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000167944	SCV004019162	likely benign	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
Baylor Genetics	RCV000167944	SCV004202061	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588409	SCV004564299	likely benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing