Submissions for variant NM_024675.4(PALB2):c.1696C>T (p.Arg566Cys)

gnomAD frequency: 0.00001  dbSNP: rs746582620

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461240	SCV000550607	uncertain significance	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 566 of the PALB2 protein (p.Arg566Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer and/or suspected Lynch syndrome (PMID: 25980754, 34326862, 35610400). ClinVar contains an entry for this variant (Variation ID: 410109). 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.
GeneDx	RCV000586825	SCV000566341	uncertain significance	not provided	2023-09-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 35610400, 34326862, 25980754)
Ambry Genetics	RCV000563652	SCV000663300	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The p.R566C variant (also known as c.1696C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 1696. The arginine at codon 566 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586825	SCV000699542	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.1696C>T (p.Arg566Cys) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/95648, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). A publication cites the variant in an affected individual, although with limited information (ie, lack of cosegregation data). A clinical diagnostic laboratory cites the variant with a classification of "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional data), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color Diagnostics, LLC DBA Color Health	RCV000563652	SCV000911952	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481446	SCV002787810	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-11-30	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000461240	SCV003807250	uncertain significance	Familial cancer of breast	2022-10-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, BP4 supporting
Baylor Genetics	RCV000461240	SCV004202045	uncertain significance	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000461240	SCV004931289	likely benign	Familial cancer of breast	2024-02-05	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].