Submissions for variant NM_024675.4(PALB2):c.2057G>A (p.Arg686Lys)

gnomAD frequency: 0.00003  dbSNP: rs267604470

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704434	SCV000833383	uncertain significance	Familial cancer of breast	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 686 of the PALB2 protein (p.Arg686Lys). This variant is present in population databases (rs267604470, gnomAD 0.01%). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 80060). 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.
Color Diagnostics, LLC DBA Color Health	RCV000774635	SCV000908481	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 686 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 colon cancer (PMID: 27978560). This variant has been identified in 1/31390 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.
Ambry Genetics	RCV000774635	SCV001174949	likely benign	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001572169	SCV001796762	uncertain significance	not provided	2020-06-24	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; Observed in individuals with colorectal cancer (Pearlman 2017); This variant is associated with the following publications: (PMID: 27978560)
Sema4, Sema4	RCV000774635	SCV002530664	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226185	SCV003923190	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2057G>A (p.Arg686Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2057G>A has been reported in the literature in at least one individual affected with colon cancer, however without strong evidence for causality (e.g., Pearlman_2017). This report therefore does not provide unequivocal conclusions about association of the variant with Prostate Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 80060). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004537269	SCV004103665	uncertain significance	PALB2-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The PALB2 c.2057G>A variant is predicted to result in the amino acid substitution p.Arg686Lys. This variant has been reported in an individual with colon cancer along with a second PALB2 variant (Patient 423046, eTable2, Pearlman et al. 2017. PubMed ID: 27978560). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641418-C-T), and is reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/80060/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001572169	SCV004222279	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31390 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 27978560 (2016)). 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.