Submissions for variant NM_024675.4(PALB2):c.20A>G (p.Lys7Arg)

gnomAD frequency: 0.00003  dbSNP: rs947155109

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483460	SCV000570094	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)
Ambry Genetics	RCV000571040	SCV000665056	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-26	criteria provided, single submitter	clinical testing	The p.K7R variant (also known as c.20A>G), located in coding exon 1 of the PALB2 gene, results from an A to G substitution at nucleotide position 20. The lysine at codon 7 is replaced by arginine, an amino acid with highly similar properties. This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702590	SCV000831449	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 7 of the PALB2 protein (p.Lys7Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 421024). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000571040	SCV000908812	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 7 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 colorectal cancer (PMID: 27978560). This variant has been identified in 1/31370 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.
Sema4, Sema4	RCV000571040	SCV002530668	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226305	SCV003923187	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.20A>G (p.Lys7Arg) 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 247972 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.20A>G 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 has been ascertained in the context of this evaluation (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 421024). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000702590	SCV004043210	likely benign	Familial cancer of breast	2023-09-28	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].
PreventionGenetics, part of Exact Sciences	RCV004527591	SCV004103006	uncertain significance	PALB2-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The PALB2 c.20A>G variant is predicted to result in the amino acid substitution p.Lys7Arg. 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/16-23652459-T-C), and is reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/421024/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000702590	SCV004202129	uncertain significance	Familial cancer of breast	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483460	SCV004222282	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000032 (1/31370 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.