Submissions for variant NM_024675.4(PALB2):c.3044C>T (p.Thr1015Ile)

gnomAD frequency: 0.00001  dbSNP: rs367840862

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130130	SCV000184963	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.T1015I variant (also known as c.3044C>T), located in coding exon 10 of the PALB2 gene, results from a C to T substitution at nucleotide position 3044. The threonine at codon 1015 is replaced by isoleucine, an amino acid with similar properties. In one study, this alteration was reported in 1/5488 control individuals and was not observed in 13087 breast cancer cases (Decker B et al. J Med Genet, 2017 11;54:732-741). 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	RCV000236113	SCV000293059	uncertain significance	not provided	2023-02-28	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; This variant is associated with the following publications: (PMID: 33471991, 28779002, 19609323, 20871615, 24485656)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689784	SCV000817451	uncertain significance	Familial cancer of breast	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1015 of the PALB2 protein (p.Thr1015Ile). This variant is present in population databases (rs367840862, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in PALB2 in at least one individual (Invitae), which suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 141554). 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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781686	SCV000919938	uncertain significance	not specified	2018-01-02	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.3044C>T (p.Thr1015Ile) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/246228 control chromosomes at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). This variant was found in at least one individual without clinical information (Decker_2017). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000130130	SCV001339377	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1015 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 28779002). This variant has been identified in 3/251446 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.
Myriad Genetics, Inc.	RCV000689784	SCV004189522	likely benign	Familial cancer of breast	2023-11-06	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	RCV000689784	SCV004202164	uncertain significance	Familial cancer of breast	2023-07-19	criteria provided, single submitter	clinical testing