Submissions for variant NM_024675.4(PALB2):c.1702C>A (p.Gln568Lys)

dbSNP: rs876659354

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214422	SCV000275725	uncertain significance	Hereditary cancer-predisposing syndrome	2015-05-11	criteria provided, single submitter	clinical testing	The p.Q568K variant (also known as c.1702C>A), located in coding exon 5 of the PALB2 gene, results from a C to A substitution at nucleotide position 1702. The glutamine at codon 568 is replaced by lysine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6497 samples (12994 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 70000 alleles tested) in our clinical cohort. 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 p.Q568K remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000214422	SCV000690803	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818865	SCV000959501	uncertain significance	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 568 of the PALB2 protein (p.Gln568Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 231775). 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%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002494593	SCV002802070	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000818865	SCV004202172	uncertain significance	Familial cancer of breast	2023-07-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701288	SCV005203560	uncertain significance	not specified	2024-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541351	SCV004786182	uncertain significance	PALB2-related disorder	2023-11-22	no assertion criteria provided	clinical testing	The PALB2 c.1702C>A variant is predicted to result in the amino acid substitution p.Gln568Lys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/231775/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.