Submissions for variant NM_024675.4(PALB2):c.950C>T (p.Thr317Ile)

gnomAD frequency: 0.00003  dbSNP: rs45548638

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164806	SCV000215486	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.T317I variant (also known as c.950C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 950. The threonine at codon 317 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in affected breast cancer patients (Rahman N et al. Nat Genet, 2007 Feb;39:165-7; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), and has also been reported in an unaffected control individual (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is poorly 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	RCV000200449	SCV000255118	uncertain significance	Familial cancer of breast	2025-01-26	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 317 of the PALB2 protein (p.Thr317Ile). This variant is present in population databases (rs45548638, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 17200668, 26976419). ClinVar contains an entry for this variant (Variation ID: 185396). 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 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	RCV000200449	SCV000489250	uncertain significance	Familial cancer of breast	2016-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000766544	SCV000565344	uncertain significance	not provided	2021-01-13	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016) In silico analysis supports that this missense variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 17200668, 26976419, 30761385)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766544	SCV000601802	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2), 26976419 (2016), 17200668 (2007)). The frequency of this variant in the general population, 0.0000071 (2/282470 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000164806	SCV000903056	benign	Hereditary cancer-predisposing syndrome	2016-03-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200449	SCV004019124	benign	Familial cancer of breast	2023-03-30	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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357471	SCV001552953	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Thr317Ile variant was identified in 2 of 2822 proband chromosomes (frequency: 0.0007) from individuals or families with breast cancer and was not identified in 2168 control chromosomes from healthy individuals (Rahman 2007, Tung 2016). The variant was also identified in dbSNP (ID: rs45548638) as "With Uncertain significance allele", and in ClinVar (classified as benign by Color; as uncertain significance by Invitae, Ambry Genetics and three other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 2 of 276984 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 126600 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr317 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.