Submissions for variant NM_024675.4(PALB2):c.3122A>C (p.Lys1041Thr)

dbSNP: rs781663559

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478421	SCV000572059	uncertain significance	not provided	2016-10-17	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.3122A>C at the cDNA level, p.Lys1041Thr (K1041T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has been observed in at least one individual with either a personal or family history of breast and/or ovarian cancer (Cao 2009). PALB2 Lys1041Thr 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 Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. PALB2 Lys1041Thr occurs at a position that is not conserved and is located within the WD4 repeat region, a region required for interaction with POLH and POLH DNA synthesis stimulation, as well as a region of interaction with RAD51 and BRCA2 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Lys1041Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635632	SCV000757052	uncertain significance	Familial cancer of breast	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 1041 of the PALB2 protein (p.Lys1041Thr). This variant is present in population databases (rs781663559, gnomAD 0.0009%). This missense change has been observed in individual(s) with pediatric acute myeloid leukemia and a personal and/or family history of breast cancer (PMID: 18446436, 31159747, 31470354). ClinVar contains an entry for this variant (Variation ID: 422560). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31586400). 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.
GeneKor MSA	RCV000708730	SCV000822114	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000708730	SCV001180010	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	The p.K1041T variant (also known as c.3122A>C), located in coding exon 11 of the PALB2 gene, results from an A to C substitution at nucleotide position 3122. The lysine at codon 1041 is replaced by threonine, an amino acid with similar properties. This alteration was reported in 1/360 Chinese women with hereditary breast cancer who previously tested negative for BRCA1 and BRCA2 mutations (Cao AY et al. Breast Cancer Res. Treat. 2009 Apr;114:457-62). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. 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.
Color Diagnostics, LLC DBA Color Health	RCV000708730	SCV001345227	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 1041 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 (PMID: 18446436) and in a breast cancer case-control meta-analysis in 1/60463 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010783). This variant has been identified in 1/250404 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.
Baylor Genetics	RCV000635632	SCV005053935	uncertain significance	Familial cancer of breast	2023-12-20	criteria provided, single submitter	clinical testing