Submissions for variant NM_024675.4(PALB2):c.2732C>A (p.Thr911Asn)

gnomAD frequency: 0.00001  dbSNP: rs180177123

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562850	SCV000666884	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-20	criteria provided, single submitter	clinical testing	The p.T911N variant (also known as c.2732C>A), located in coding exon 7 of the PALB2 gene, results from a C to A substitution at nucleotide position 2732. The threonine at codon 911 is replaced by asparagine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685459	SCV000812941	uncertain significance	Familial cancer of breast	2023-09-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 911 of the PALB2 protein (p.Thr911Asn). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 482014). 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.
Color Diagnostics, LLC DBA Color Health	RCV000562850	SCV001352895	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 911 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844198	SCV002103989	uncertain significance	not specified	2022-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000685459	SCV004202062	uncertain significance	Familial cancer of breast	2023-09-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478238	SCV004222313	uncertain significance	not provided	2022-10-03	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). 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.