Submissions for variant NM_024675.4(PALB2):c.2732C>T (p.Thr911Ile)

dbSNP: rs180177123

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589395	SCV000211521	uncertain significance	not provided	2014-05-22	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.2732C>T at the cDNA level, p.Thr911Ile (T911I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has been previously reported in a patient with early onset pancreatic cancer with no family history (Tischkowitz 2009). PALB2 Thr911Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Thr911Ile occurs at a position that is moderately conserved across species and is located in the WD1 repeat domain, the region responsible for interaction with RAD51, BRCA2 and POLH (Uniprot). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PALB2 Thr911Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000454363	SCV000538156	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The p.T911I variant (also known as c.2732C>T), located in coding exon 7 of the PALB2 gene, results from a C to T substitution at nucleotide position 2732. The threonine at codon 911 is replaced by isoleucine, an amino acid with similar properties. This variant was observed in 1/287 patients with hereditary breast and/or ovarian cancer; this patient was diagnosed with breast cancer at age 56 and had a family history of breast cancer (Caminsky NG et al. Hum. Mutat., 2016 07;37:640-52). In another study, this variant was seen in 1/254 cases with pancreatic adenocarcinoma; this individual was diagnosed with young-onset pancreas cancer and did not have a family history of cancer (Tischkowitz MD et al. Gastroenterology, 2009 Sep;137:1183-6). 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	RCV000114553	SCV000633371	uncertain significance	Familial cancer of breast	2023-12-15	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 911 of the PALB2 protein (p.Thr911Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pancreatic cancer, prostate cancer, colorectal cancer, and breast cancer (PMID: 19635604, 26898890; Invitae). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (PMID: 19635604, 26898890; Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 126676). 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	RCV000589395	SCV000699575	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.2732C>T (p.Thr911Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). PALB2 Thr911Ile alters an amino acid that is moderately conserved across species and is located in the WD40 repeat domain, the region responsible for interaction with RAD51, BRCA2, and POLH (Uniprot). This variant is absent in 121368 control chromosomes, but has been reported in one young-onset pancreas cancer case with no family history (Tischkowitz_Gastroenterology_2009) and one HBOC patient (Caminsky_ATM_Hum Mut_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. Because of limited clinical information and lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000454363	SCV000908465	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine 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 been reported in an individual affected with breast cancer with family history of the disease (PMID: 26898890) and an individual affected with pancreatic cancer (PMID: 19635604). 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.
Baylor Genetics	RCV000114553	SCV005053892	uncertain significance	Familial cancer of breast	2024-02-13	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114553	SCV001193280	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.